Phosphodiesterase 4 inhibitors

ABSTRACT

Selective PDE4 inhibition is achieved by aryl and heteroaryl pyrazole compounds. The compounds exhibit improved PDE4 inhibition as compared to compounds such as rolipram and show selectivity with regard to inhibition of other classes of PDEs.

This application claims the benefit of U.S. Provisional Application Ser.No. 60/618,725, filed Oct. 15, 2004, the entire disclosure of which ishereby incorporated by reference.

This application is related to copending U.S. application Ser. No.10/825,611, filed Apr. 16, 2004, which claims the benefit of U.S.Provisional Application Ser. No. 60/463,725, filed Apr. 18, 2003, theentire disclosures of each of which are hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention relates generally to the field ofphosphodiesterase 4 (PDE4) enzyme inhibition. More specifically, thisinvention relates to selective PDE4 inhibition by novel compounds, e.g.,aryl and heteroaryl substituted pyrazole compounds, methods of preparingsuch compounds, compositions containing such compounds, and methods ofuse thereof.

BACKGROUND OF THE INVENTION

The cyclic nucleotide specific phosphodiesterases (PDEs) represent afamily of enzymes that catalyze the hydrolysis of various cyclicnucleoside monophosphates (including cAMP and cGMP). These cyclicnucleotides act as second messengers within cells, and as messengers,carry impulses from cell surface receptors having bound various hormonesand neurotransmitters. PDEs act to regulate the level of cyclicnucleotides within cells and maintain cyclic nucleotide homeostasis bydegrading such cyclic mononucleotides resulting in termination of theirmessenger role.

PDE enzymes can be grouped into eleven families according to theirspecificity toward hydrolysis of cAMP or cGMP, their sensitivity toregulation by calcium, calmodulin or cGMP, and their selectiveinhibition by various compounds. For example, PDE1 is stimulated byCa²⁺/calmodulin. PDE2 is cGMP-dependent, and is found in the heart andadrenals. PDE3 is cGMP-inhibited, and inhibition of this enzyme createspositive inotropic activity. PDE4 is cAMP specific, and its inhibitioncauses airway relaxation, anti-inflammatory and antidepressant activity.PDE5 appears to be important in regulating cGMP content in vascularsmooth muscle, and therefore PDE5 inhibitors may have cardiovascularactivity. Since the PDEs possess distinct biochemical properties, it islikely that they are subject to a variety of different forms ofregulation.

PDE4 is distinguished by various kinetic properties including lowMichaelis constant for cAMP and sensitivity to certain drugs. The PDE4enzyme family consists of four genes, which produce 4 isoforms of thePDE4 enzyme designated PDE4A, PDE4B, PDE4C, and PDE4D [Wang et al.,Expression, Purification, and Characterization of Human cAMP-SpecificPhosphodiesterase (PDE4) Subtypes A, B, C, and D, Biochem. Biophys. Res.Comm., 234, 320-324 (1997)]. In addition, various splice variants ofeach PDE4 isoform have been identified.

PDE4 isoenzymes are localized in the cytosol of cells and areunassociated with any known membranous structures. PDE4 isoenzymesspecifically inactivate cAMP by catalyzing its hydrolysis to adenosine5′-monophosphate (AMP). Regulation of cAMP activity is important in manybiological processes, including inflammation and memory. Inhibitors ofPDE4 isoenzymes such as rolipram, piclamilast, CDP-840 and ariflo arepowerful anti-inflammatory agents and therefore may be useful intreating diseases where inflammation is problematic such as asthma orarthritis. Further, rolipram improves the cognitive performance of ratsand mice in learning paradigms.

In addition to such compounds as rolipram, xanthine derivatives such aspentoxifylline, denbufylline, and theophylline inhibit PDE4 and havereceived attention of late for their cognition enhancing effects. cAMPand cGMP are second messengers that mediate cellular responses to manydifferent hormones and neurotransmitters. Thus, therapeuticallysignificant effects may result from PDE inhibition and the resultingincrease in intracellular cAMP or cGMP in key cells, such as thoselocated in the nervous system and elsewhere in the body.

Rolipram, previously in development as an antidepressant, selectivelyinhibits the PDE4 enzyme and has become a standard agent in theclassification of PDE enzyme subtypes. Early work in the PDE4 fieldfocused on depression and inflammation, and has subsequently beenextended to include indications such as dementia. [see “The PDE IVFamily Of Calcium-Phosphodiesterases Enzymes,” John A. Lowe, III, etal., Drugs of the Future 1992, 17(9): 799-807 for a general review].Further clinical developments of rolipram and other first-generationPDE4 inhibitors were terminated due to the side effect profile of thesecompounds. The primary side effect in primates is emesis, while theprimary side effects in rodents are testicular degranulation, weakeningof vascular smooth muscle, psychotrophic effects, increased gastric acidsecretion, and stomach erosion. In humans, the primary side effect isnausea and emesis. Thus, there is a continuing need to develop selectivePDE4 inhibitors with improved side effect profiles (e.g., are relativelynon-emetic) while retaining therapeutic utility.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds that inhibit,preferably selectively, PDE4 enzymes, and especially have improved sideeffect profiles, e.g., are relatively non-emetic (e.g., as compared tothe previously discussed prior art compounds). In particular, thepresent invention relates to aryl and heteroaryl substituted pyrazolecompounds. The compounds of this invention at the same time facilitateentry into cells, especially cells of the nervous system.

Still further, the present invention provides methods for synthesizingcompounds with such activity and selectivity, as well as methods of andcorresponding pharmaceutical compositions for treating a patient, e.g.,mammals, including humans, in need of PDE inhibition. Treatment ispreferably for a disease state that involves elevated intracellular PDE4levels or decreased cAMP levels, e.g., involving neurological syndromes,especially those states associated with depression and/or memoryimpairment, most especially major depression and/or long term memoryimpairment. In particular, such depression and/or memory impairment isdue at least in part to catabolism of intracellular cAMP levels by PDE4enzymes or where such an impaired condition can be improved byincreasing cAMP levels. In a preferred aspect, the compounds of theinventions improve such diseases by inhibiting PDE4 enzymes at dosesthat do not induce emesis or other side effects.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to selective PDE4 inhibition by novelcompounds, e.g., aryl and heteroaryl substituted pyrazole compounds,methods of preparing such compounds, compositions containing suchcompounds, and methods of use thereof.

The present invention includes compounds selected from Formulas I, II,III, IV, V, VI, VII, VIII, IX or X:

wherein

-   -   X is CH or N;    -   L is a single bond; C₁-C₆ straight chain or branched alkylene,        wherein a CH₂ group is optionally replaced by O, NH, NR¹, or S,        which is unsubstituted or substituted one or more times by oxo,        halogen (preferably F), hydroxy, cyano or combinations thereof;        (CH₂)_(n)CONH; (CH₂)_(n)OCONH; (CH₂)_(n)CON(C₁₋₆-alkyl);        (CH₂)_(n)NHCO; (CH₂)_(n)CONHSO₂; (CH₂)_(n)SO₂NH; (CH₂)_(n)SO₂;        or (CH₂)_(n)CO₂ (e.g., a bond, CH₂CONH, SO₂, CH₂CO₂, CH₂CO);    -   n is 0 to 3;    -   R¹ is alkyl having 1 to 4 carbon atoms, which is unsubstituted        or substituted one or more times by halogen (e.g., CH₃, CHF₂);    -   R² is H,        -   alkyl having 1 to 8 carbon atoms, which is unsubstituted or            substituted one or more times by halogen, oxo or            combinations thereof wherein optionally one or more —CH₂CH₂—            groups are replaced in each case by —CH═CH— or —C≡C— groups            (e.g., CH₃, CHF₂),        -   cycloalkyl having 3 to 8 carbon atoms, which is            unsubstituted or substituted one or more times by halogen,            oxo, alkyl having 1 to 4 carbon atoms or combinations            thereof (e.g., cyclopentyl),        -   a heterocyclic group, which is saturated, partially            saturated or fully unsaturated, having 5 to 10 ring atoms in            which at least 1 ring atom is an N, O or S atom (e.g.,            3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is            unsubstituted or substituted one or more times by halogen,            aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g.,            trifluoromethyl), nitro, oxo, amino, alkylamino,            dialkylamino, or combinations thereof (e.g.,            tetrahydrofuranyl),        -   aryl having 6 to 14 carbon atoms, which is unsubstituted or            substituted one or more times by halogen, CF₃, OCF₃, alkyl,            hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy,            amino, alkylamino, dialkylamino, hydroxyalkyl,            hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl,            alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido            (e.g., acetamido), and acyloxy (e.g., acetoxy), or            combinations thereof,        -   arylalkyl having 7 to 16 carbon atoms, which is            unsubstituted or substituted, preferably in the aryl            portion, one or more times by halogen, CF₃, OCF₃, alkyl,            hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy,            amino, alkylamino, dialkylamino, hydroxyalkyl,            hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl,            alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido            (e.g., acetamido), and acyloxy (e.g., acetoxy), or            combinations thereof (e.g., benzyl, difluorobenzyl),        -   a partially unsaturated carbocyclic group having 5 to 14            carbon atoms, (e.g., cyclohexenyl, cyclohexadienyl, indanyl,            and tetrahydronaphthenyl), which is unsubstituted or            substituted one or more times by halogen, alkyl, alkoxy,            nitro, cyano, oxo, or combinations thereof,        -   arylalkenyl having 8 to 16 carbon atoms, wherein the alkenyl            portion has up to 5 carbon atoms, which is unsubstituted or            substituted, preferably in the aryl portion, one or more            times by halogen, alkyl, hydroxy, alkoxy, nitro,            methylenedioxy, ethylenedioxy, amino, alkylamino,            dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano,            acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl,            alkylsulfonyl, phenoxy, acylamido (e.g., acetamido), and            acyloxy (e.g., acetoxy), or combinations thereof,        -   a heterocyclic-alkyl group, which is saturated, partially            saturated or fully unsaturated, having 5 to 10 ring atoms in            which at least 1 ring atom is an N, O or S atom, which is            unsubstituted or substituted one or more times in the            heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano,            halogenated alkyl (e.g., trifluoromethyl), nitro, oxo,            amino, alkylamino, dialkylamino, carboxy or combinations            thereof and/or substituted in the alkyl portion by halogen,            oxo, cyano, or combinations thereof, or        -   cycloalkylalkyl having 4 to 16 carbon atoms (e.g.,            cyclopentylethyl and cyclopropylmethyl), which is            unsubstituted or substituted one or more times by halogen,            oxo, alkyl or combinations thereof;    -   R³ is H,        -   alkyl having 1 to 8 carbon atoms, which is unsubstituted or            substituted one or more times by halogen, oxo, or            combinations thereof wherein optionally one or more —CH₂CH₂—            groups are replaced in each case by —CH═CH— or —C≡C— groups            (e.g., C₂H₅, CH(CH₃)₂, n-propyl, n-butyl, t.-butyl),            cycloalkyl having 3 to 8 carbon atoms, which is            unsubstituted or substituted one or more times by halogen,            oxo, alkyl, or combinations thereof (e.g., cyclopentyl,            cyclohexyl),        -   aryl having 6 to 14 carbon atoms, which is unsubstituted or            substituted one or more times by halogen, alkyl, hydroxy,            alkoxy, halogenated alkyl, halogenated alkoxy (e.g., OCF₃),            nitro, methylenedioxy, ethylenedioxy, amino, alkylamino,            dialkylamino, —CO—N(R¹⁰)₂, —SO₂—N(R¹⁰)₂, hydroxyalkyl,            hydroxyalkoxy (e.g., —OCH₂HC₂OH), alkoxyalkoxy (e.g.,            methoxyethoxy (CH₃OCH₂CH₂O—), alkoxyalkoxyalkyl (e.g.,            CH₃OCH₂CH₂OCH₂—), carboxy, cyano, acyl, alkoxycarbonyl,            alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,            arylsulfonyl, aminosulfonyl, phenyl, halogenated phenyl,            phenoxy, benzyloxy, acyloxy (e.g., acetoxy), acylamido            (e.g., acetamido), furanyl which is unsubstituted or            substituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy,            C₂₋₈-alkoxycarbonyl, and/or benzyl, pyrrolyl which is            unsubstituted or substituted by halogen, C₁₋₄-alkyl,            C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl, pyrazolyl            which is unsubstituted or substituted by halogen,            C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl,            isoxazolyl which is unsubstituted or substituted by halogen,            C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl,            imidazolyl which is unsubstituted or substituted by halogen,            C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl,            pyridinyl which is unsubstituted or substituted by halogen,            C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl,            pyrimidinyl which is unsubstituted or substituted by            halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl,            and/or benzyl, morpholinyl which is unsubstituted or            substituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or            benzyl, piperadinyl which is unsubstituted or substituted by            C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or benzyl, piperazinyl            which is unsubstituted or substituted by C₁₋₄-alkyl,            C₂₋₈-alkoxycarbonyl, and/or benzyl, tetrazolyl which is            unsubstituted or substituted by C₁₋₄-alkyl,            C₂₋₈-alkoxycarbonyl, and/or benzyl, alkylsulphonimide (e.g.,            CH₃SO₂—NHCO—), arylsulphonimide (e.g., C₆H₅SO₂—NHCO—)            wherein the aryl portion is optionally substituted by            halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, or combinations thereof            (e.g., phenyl, bromophenyl, cyanophenyl, nitrophenyl,            fluorophenyl, difluorophenyl, trifluoromethoxyphenyl,            methylphenyl, dimethylphenyl, methoxyphenyl, biphenyl            substituted by —CONH₂, and phenyl substituted by biphenyl or            —CONH₂),        -   heterocyclic group, which is saturated, partially saturated            or fully unsaturated, having 5 to 10 ring atoms in which at            least 1 ring atom is an N, O or S atom, which is            unsubstituted or substituted one or more times by halogen,            alkyl, hydroxy, alkoxy, halogenated alkyl (e.g.,            trifluoromethyl), halogenated alkoxy, nitro, methylenedioxy,            ethylenedioxy, amino, alkylamino, dialkylamino,            hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl,            alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl,            arylsulfinyl, arylsulfonyl, phenyl, halogenated phenyl,            phenoxy, acyloxy, tetrazolyl, alkylsulphonimide,            arylsulphonimide, aryl, oxo, acylamido (e.g., acetamido), or            combinations thereof (e.g., pyridyl, methylpyridyl,            benzothiazolyl),        -   arylalkyl having 7 to 16 carbon atoms, which is            unsubstituted or substituted, preferably in the aryl            portion, one or more times by halogen, alkyl, hydroxy,            alkoxy, halogenated alkyl (e.g. CF₃), halogenated alkoxy            (e.g. OCF₃), nitro, methylenedioxy, ethylenedioxy, amino,            alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy,            carboxy, cyano, acyl, alkoxycarbonyl, alkylthio,            alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl,            phenyl, halogenated phenyl, phenoxy, acyloxy (e.g.,            acetoxy), acylamido (e.g., acetamido), tetrazolyl,            alkylsulphonimide, arylsulphonimide, or combinations thereof            and/or substituted in the alkyl portion by halogen, oxo,            cyano, or combinations thereof (e.g., benzyl, methylbenzyl,            t.-butylbenzyl, methoxybenzyl, dimethoxybenzyl,            fluorobenzyl, difluorobenzyl, trifluoromethylbenzyl,            trifluoromethoxybenzyl, chlorobenzyl, aminobenzyl,            nitrobenzyl, methoxycarbonylbenzyl, methylsulfonylbenzyl,            phenethyl, phenpropyl),        -   a heterocyclic-alkyl group, which is saturated, partially            saturated or fully unsaturated, having 5 to 10 ring atoms in            which at least 1 ring atom is an N, O or S atom, which is            unsubstituted or substituted one or more times in the            heterocyclic portion by halogen, alkyl, hydroxy, alkoxy,            halogenated alkyl (e.g., trifluoromethyl), halogenated            alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,            alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy,            carboxy, cyano, acyl, alkoxycarbonyl, alkylthio,            alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl,            phenyl, halogenated phenyl, phenoxy, acyloxy, tetrazolyl,            alkylsulphonimide, arylsulphonimide, aryl, oxo, or            combinations thereof and/or substituted in the alkyl portion            by halogen, oxo, cyano, or combinations thereof (e.g.,            pyridylmethyl),        -   cycloalkylalkyl having 4 to 16 carbon atoms (e.g.,            cyclopentylethyl and cyclopropylmethyl), which is            unsubstituted or substituted one or more times by halogen,            oxo, alkyl or combinations thereof, or        -   alkoxyalkyl having 3 to 8 carbon atoms;    -   R⁴ is alkyl having 1 to 6 carbon atoms, which is unsubstituted        or substituted one or more times by halogen, oxo, or        combinations thereof wherein optionally one or more —CH₂CH₂—        groups are replaced in each case by —CH═CH— or —C≡C— groups        (e.g., CH₃);    -   R⁵ is H, or        -   alkyl having 1 to 6 carbon atoms, which is unsubstituted or            substituted one or more times by halogen wherein optionally            one or more —CH₂CH₂— groups are replaced in each case by            —CH═CH— or —C≡C— groups (e.g., CH₃, C₂H₅);    -   R⁶ is H,        -   alkyl having 1 to 6 carbon atoms, which is unsubstituted or            substituted one or more times by halogen, oxo, hydroxy or            combinations thereof wherein optionally one or more —CH₂CH₂—            groups are replaced in each case by —CH═CH— or —C≡C— groups,        -   alkoxyalkyl having 2 to 6 carbon atoms (e.g., methoxyethyl            (CH₂CH₂OCH₃), ethoxymethyl (CH₂OCH₂CH₃)), which is            unsubstituted or substituted one or more times by halogen,            oxo, or combinations thereof;        -   alkoxycarbonyl (—C(═O)O-alkyl) having 2 to 6 carbon atoms            (e.g., —C(═O)OCH(CH₃)₂);        -   —CO—NR⁵R¹²;        -   cycloalkyl having 3 to 8 carbon atoms, which is            unsubstituted or substituted one or more times by halogen,            oxo, alkyl, or combinations thereof (e.g., cyclopentyl),        -   cycloalkylalkyl having 4 to 16 carbon atoms (e.g.,            cyclopentylethyl and cyclopropylmethyl), which is            unsubstituted or substituted one or more times by halogen,            oxo, alkyl or combinations thereof,        -   aryl having 6 to 14 carbon atoms, which is unsubstituted or            substituted one or more times by halogen, CF₃, OCF₃, alkyl,            hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy,            amino, alkylamino, dialkylamino, hydroxyalkyl,            hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl,            alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido            (e.g., acetamido), and acyloxy (e.g., acetoxy), or            combinations thereof,        -   arylalkyl having 7 to 16 carbon atoms, which is            unsubstituted or substituted, preferably in the aryl            portion, one or more times by halogen, CF₃, OCF₃, alkyl,            hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy,            amino, alkylamino, dialkylamino, hydroxyalkyl,            hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl,            alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido            (e.g., acetamido), and acyloxy (e.g., acetoxy), or            combinations thereof,        -   a heterocyclic group, which is saturated, partially            saturated or fully unsaturated, having 5 to 10 ring atoms in            which at least 1 ring atom is an N, O or S atom (e.g.,            3-thienyl, 2-thienyl, 3-tetrahydrofuranyl, 2-pyrimidinyl,            4-tetrahydropyranyl), which is unsubstituted or substituted            one or more times by halogen, aryl, alkyl, alkoxy,            alkoxycarbonyl, cyano, halogenated alkyl (e.g.,            trifluoromethyl), nitro, oxo, amino, alkylamino,            dialkylamino, or combinations thereof, or        -   a heterocyclic-alkyl group, which is saturated, partially            saturated or filly unsaturated, having 5 to 10 ring atoms in            which at least 1 ring atom is an N, O or S atom, which is            unsubstituted or substituted one or more times in the            heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano,            halogenated alkyl (e.g., trifluoromethyl), nitro, oxo,            amino, alkylamino, dialkylamino, carboxy or combinations            thereof and/or substituted in the alkyl portion by halogen,            oxo, cyano, or combinations thereof;    -   R⁷ is H, halogen, or alkyl having 1 to 6 carbon atoms wherein        optionally one or more —CH₂CH₂— groups are replaced in each case        by —CH═CH— or —C≡C— groups and wherein the alkyl is        unsubstituted or substituted one or more times by halogen;    -   R⁸ is H, halogen, alkyl having 1 to 6 carbon atoms wherein        optionally one or more —CH₂CH₂— groups are replaced in each case        by —CH═CH— or —C≡C— groups and wherein the alkyl is        unsubstituted or substituted one or more times by halogen or        hydroxyl (e.g., CH₃, C₂H₅, CF₃, hydroxymethyl,        2-(2-hydroxy)propyl, hydroxymethyl), carboxy, alkoxycarbonyl        having 2 to 6 carbon atoms (e.g., ethoxycarbonyl), —CO-alkyl        having 2 to 6 carbon atoms (e.g., CH₃CO), or phenyl;    -   R⁹ is halogen (e.g., F); and    -   R¹⁰ is H,        -   alkyl having 1 to 8 carbon atoms, which is unsubstituted or            substituted one or more times by halogen, oxo or            combinations thereof wherein optionally one or more —CH₂CH₂—            groups are replaced in each case by —CH═CH— or —C≡C— groups            (e.g., CH₃, CHF₂), or    -   alkoxy having 2 to 8 carbon atoms, which is unsubstituted or        substituted one or more times by halogen;    -   R¹¹ is H,        -   alkyl having 1 to 6 carbon atoms (e.g., methyl,            ethylpropyl), which is unsubstituted or substituted one or            more times by halogen, oxo, or combinations thereof wherein            optionally one or more —CH₂CH₂— groups are replaced in each            case by —CH═CH— or —C≡C— groups (e.g., CH₃, C₂H₅), or        -   a heterocyclic-alkyl group, which is saturated, partially            saturated or fully unsaturated, having 5 to 10 ring atoms in            which at least 1 ring atom is an N, O or S atom, which is            unsubstituted or substituted one or more times in the            heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano,            halogenated alkyl (e.g., trifluoromethyl), nitro, oxo,            amino, alkylamino, dialkylamino, carboxy or combinations            thereof and/or substituted in the alkyl portion by halogen,            oxo, cyano, or combinations thereof (e.g.,            tetrahydro-2H-pyranylmethyl, pyrollidinylethyl;    -   R¹² is H,        -   alkyl having 1 to 6 carbon atoms (e.g., methyl,            ethylpropyl), which is unsubstituted or substituted one or            more times by halogen, oxo, or combinations thereof wherein            optionally one or more —CH₂CH₂— groups are replaced in each            case by —CH═CH— or —C≡C— groups (e.g., CH₃, C₂H₅),        -   cycloalkyl having 3 to 8 carbon atoms, which is            unsubstituted or substituted one or more times by halogen,            oxo, alkyl, or combinations thereof (e.g., cyclopentyl), or        -   a heterocyclic-alkyl group, which is saturated, partially            saturated or fully unsaturated, having 5 to 10 ring atoms in            which at least 1 ring atom is an N, O or S atom, which is            unsubstituted or substituted one or more times in the            heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano,            halogenated alkyl (e.g., trifluoromethyl), nitro, oxo,            amino, alkylamino, dialkylamino, carboxy or combinations            thereof and/or substituted in the alkyl portion by halogen,            oxo, cyano, or combinations thereof (e.g., furylmethyl);

and pharmaceutically acceptable salts or solvates (e.g., hydrates)thereof, or solvates of pharmaceutically acceptable salts thereof.

According to a further compound aspect of the invention, the compoundsare of formulas I, II, III, IV, V, VI, VII or VIII, wherein L is(CH₂)_(n)OCONH, particularly compounds of formula IV wherein L is(CH₂)_(n)OCONH.

According to a further compound aspect of the invention, the compoundsare of formulas I, II, III, IV, V, VI, VII or VIII, particularly IV andVI, wherein R³ is aryl having 6 to 14 carbon atoms (particularly phenylor biphenyl), which is substituted by at least one substituent selectedfrom —CO—N(R¹⁰)₂ (wherein R¹⁰ is preferably, H, alkyl or alkoxy),aminosulfonyl, furanyl which is unsubstituted or substituted by halogen,C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl and/or benzyl, pyrrolylwhich is unsubstituted or substituted by halogen, C₁₋₄-alkyl,C₂₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl, pyrazolyl which issubstituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl,and/or benzyl, isoxazolyl which is unsubstituted or substituted byhalogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl,imidazolyl which is substituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy,C₂₋₈-alkoxycarbonyl, and/or benzyl, pyridinyl which is substituted byhalogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl,pyrimidinyl which is unsubstituted or substituted by halogen,C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl, morpholinylwhich is substituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or benzyl,piperadinyl which is substituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl,and/or benzyl, piperazinyl which is substituted by C₁₋₄-alkyl,C₂₋₈-alkoxycarbonyl, and/or benzyl, tetrazolyl which is unsubstituted orsubstituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or benzyl, orarylsulphonimide (e.g., C₆H₅SO₂—NHCO—) wherein the aryl portion issubstituted by halogen or C₁₋₄-alkoxy.

According to a further compound aspect of the invention, the compoundsare of Formula IX or X, e.g., Formula IX.

According to a further compound aspect of the invention, the compoundsare of formulas I, II, III, IV, V, VI, VII or VIII, particularly IV andVI, wherein R³ is aryl substituted at least once by —SO₂—N(R¹⁰)₂,alkoxyalkoxy (e.g., methoxyethoxy), alkoxyalkoxyalkyl (e.g.,CH₃OCH₂CH₂OCH₂—) or benzyloxy.

According to a further compound aspect of the invention, the compoundsare of formulas III or VI, wherein R⁶ is alkyl having 1 to 6 carbonatoms which is substituted at least once by hydroxy; alkoxyalkyl having2 to 6 carbon atoms (e.g., methoxyethyl, ethoxymethyl), which isunsubstituted or substituted one or more times by halogen, oxo, orcombinations thereof; alkoxycarbonyl (—C(═O)O-alkyl) having 2 to 6carbon atoms (e.g., —C(═O)OCH(CH₃)₂); or —CO—NR⁵R¹².

In accordance with the method aspect of the invention, there is provideda method of treating a patient (e.g., a mammal such as a human)suffering from a disease state (e.g., memory impairment) involvingdecreased cAMP levels and/or increased intracellular PDE4 levels,comprising administering to the patient a compound selected fromFormulas I, II, III, IV, V, VI, VII, VIII, IX or X:

wherein

-   -   X is CH or N;    -   L is a single bond; C₁-C₆ straight chain or branched alkylene,        wherein a CH₂ group is optionally replaced by O, NH, NR¹, or S,        which is unsubstituted or substituted one or more times by oxo,        halogen (preferably F), hydroxy, cyano or combinations thereof;        (CH₂)_(n)CONH; (CH₂)_(n)OCONH; (CH₂)_(n)CON(C₁₋₆-alkyl);        (CH₂)_(n)NHCO; (CH₂)_(n)CONHSO₂; (CH₂)_(n)SO₂NH; (CH₂)_(n)SO₂;        or (CH₂)_(n)CO₂ (e.g., a bond, CH₂CONH, SO₂, CH₂CO₂, CH₂CO);    -   n is 0 to 3;    -   R¹ is alkyl having 1 to 4 carbon atoms, which is unsubstituted        or substituted one or more times by halogen (e.g., CH₃, CHF₂);    -   R² is H,        -   alkyl having 1 to 8 carbon atoms, which is unsubstituted or            substituted one or more times by halogen, oxo or            combinations thereof wherein optionally one or more —CH₂CH₂—            groups are replaced in each case by —CH═CH— or —C≡C— groups            (e.g., CH₃, CHF₂),        -   cycloalkyl having 3 to 8 carbon atoms, which is            unsubstituted or substituted one or more times by halogen,            oxo, alkyl having 1 to 4 carbon atoms or combinations            thereof (e.g., cyclopentyl),        -   a heterocyclic group, which is saturated, partially            saturated or fully unsaturated, having 5 to 10 ring atoms in            which at least 1 ring atom is an N, O or S atom (e.g.,            3-thienyl, 2-thienyl, 3-tetrahydrofuranyl), which is            unsubstituted or substituted one or more times by halogen,            aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g.,            trifluoromethyl), nitro, oxo, amino, alkylamino,            dialkylamino, or combinations thereof (e.g.,            tetrahydrofuranyl),        -   aryl having 6 to 14 carbon atoms, which is unsubstituted or            substituted one or more times by halogen, CF₃, OCF₃, alkyl,            hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy,            amino, alkylamino, dialkylamino, hydroxyalkyl,            hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl,            alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido            (e.g., acetamido), and acyloxy (e.g., acetoxy), or            combinations thereof,        -   arylalkyl having 7 to 16 carbon atoms, which is            unsubstituted or substituted, preferably in the aryl            portion, one or more times by halogen, CF₃, OCF₃, alkyl,            hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy,            amino, alkylamino, dialkylamino, hydroxyalkyl,            hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl,            alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido            (e.g., acetamido), and acyloxy (e.g., acetoxy), or            combinations thereof (e.g., benzyl, difluorobenzyl),        -   a partially unsaturated carbocyclic group having 5 to 14            carbon atoms, (e.g., cyclohexenyl, cyclohexadienyl, indanyl,            and tetrahydronaphthenyl), which is unsubstituted or            substituted one or more times by halogen, alkyl, alkoxy,            nitro, cyano, oxo, or combinations thereof,        -   arylalkenyl having 8 to 16 carbon atoms, wherein the alkenyl            portion has up to 5 carbon atoms, which is unsubstituted or            substituted, preferably in the aryl portion, one or more            times by halogen, alkyl, hydroxy, alkoxy, nitro,            methylenedioxy, ethylenedioxy, amino, alkylamino,            dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano,            acyl, alkoxycarbonyl, alkylthio, alkylsulfinyl,            alkylsulfonyl, phenoxy, acylamido (e.g., acetamido), and            acyloxy (e.g., acetoxy), or combinations thereof,        -   a heterocyclic-alkyl group, which is saturated, partially            saturated or fully unsaturated, having 5 to 10 ring atoms in            which at least 1 ring atom is an N, O or S atom, which is            unsubstituted or substituted one or more times in the            heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano,            halogenated alkyl (e.g., trifluoromethyl), nitro, oxo,            amino, alkylamino, dialkylamino, carboxy or combinations            thereof and/or substituted in the alkyl portion by halogen,            oxo, cyano, or combinations thereof, or        -   cycloalkylalkyl having 4 to 16 carbon atoms (e.g.,            cyclopentylethyl and cyclopropylmethyl), which is            unsubstituted or substituted one or more times by halogen,            oxo, alkyl or combinations thereof;    -   R³ is H,        -   alkyl having 1 to 8 carbon atoms, which is unsubstituted or            substituted one or more times by halogen, oxo, or            combinations thereof wherein optionally one or more —CH₂CH₂—            groups are replaced in each case by —CH═CH— or —C≡C— groups            (e.g., C₂H₅, CH(CH₃)₂, n-propyl, n-butyl, t.-butyl),        -   cycloalkyl having 3 to 8 carbon atoms, which is            unsubstituted or substituted one or more times by halogen,            oxo, alkyl, or combinations thereof (e.g., cyclopentyl,            cyclohexyl),        -   aryl having 6 to 14 carbon atoms, which is unsubstituted or            substituted one or more times by halogen, alkyl, hydroxy,            alkoxy, halogenated alkyl, halogenated alkoxy (e.g., OCF₃),            nitro, methylenedioxy, ethylenedioxy, amino, alkylamino,            dialkylamino, —CO—N(R¹⁰)₂, —SO₂—N(R¹⁰)₂, hydroxyalkyl,            hydroxyalkoxy (e.g., —OCH₂HC₂OH), alkoxyalkoxy (e.g.,            methoxyethoxy (CH₃OCH₂CH₂O—), alkoxyalkoxyalkyl (e.g.,            CH₃OCH₂CH₂OCH₂—), carboxy, cyano, acyl, alkoxycarbonyl,            alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,            arylsulfonyl, aminosulfonyl, phenyl, halogenated phenyl,            phenoxy, benzyloxy, acyloxy (e.g., acetoxy), acylamido            (e.g., acetamido), furanyl which is unsubstituted or            substituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy,            C₂₋₈-alkoxycarbonyl, and/or benzyl, pyrrolyl which is            unsubstituted or substituted by halogen, C₁₋₄-alkyl,            C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl, pyrazolyl            which is unsubstituted or substituted by halogen,            C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl,            isoxazolyl which is unsubstituted or substituted by halogen,            C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl,            imidazolyl which is unsubstituted or substituted by halogen,            C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl,            pyridinyl which is unsubstituted or substituted by halogen,            C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl,            pyrimidinyl which is unsubstituted or substituted by            halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl,            and/or benzyl, morpholinyl which is unsubstituted or            substituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or            benzyl, piperadinyl which is unsubstituted or substituted by            C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or benzyl, piperazinyl            which is unsubstituted or substituted by C₁₋₄-alkyl,            C₂₋₈-alkoxycarbonyl, and/or benzyl, tetrazolyl which is            unsubstituted or substituted by C₁₋₄-alkyl,            C₂₋₈-alkoxycarbonyl, and/or benzyl, alkylsulphonimide (e.g.,            CH₃SO₂—NHCO—), arylsulphonimide (e.g., C₆H₅SO₂—NHCO—)            wherein the aryl portion is optionally substituted by            halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, or combinations thereof            (e.g., phenyl, bromophenyl, cyanophenyl, nitrophenyl,            fluorophenyl, difluorophenyl, trifluoromethoxyphenyl,            methylphenyl, dimethylphenyl, methoxyphenyl, biphenyl            substituted by —CONH₂, and phenyl substituted by biphenyl or            —CONH₂),        -   heterocyclic group, which is saturated, partially saturated            or fully unsaturated, having 5 to 10 ring atoms in which at            least 1 ring atom is an N, O or S atom, which is            unsubstituted or substituted one or more times by halogen,            alkyl, hydroxy, alkoxy, halogenated alkyl (e.g.,            trifluoromethyl), halogenated alkoxy, nitro, methylenedioxy,            ethylenedioxy, amino, alkylamino, dialkylamino,            hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl,            alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl,            arylsulfinyl, arylsulfonyl, phenyl, halogenated phenyl,            phenoxy, acyloxy, tetrazolyl, alkylsulphonimide,            arylsulphonimide, aryl, oxo, acylamido (e.g., acetamido), or            combinations thereof (e.g., pyridyl, methylpyridyl,            benzothiazolyl),        -   arylalkyl having 7 to 16 carbon atoms, which is            unsubstituted or substituted, preferably in the aryl            portion, one or more times by halogen, alkyl, hydroxy,            alkoxy, halogenated alkyl (e.g. CF₃), halogenated alkoxy            (e.g. OCF₃), nitro, methylenedioxy, ethylenedioxy, amino,            alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy,            carboxy, cyano, acyl, alkoxycarbonyl, alkylthio,            alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl,            phenyl, halogenated phenyl, phenoxy, acyloxy (e.g.,            acetoxy), acylamido (e.g., acetamido), tetrazolyl,            alkylsulphonimide, arylsulphonimide, or combinations thereof            and/or substituted in the alkyl portion by halogen, oxo,            cyano, or combinations thereof (e.g., benzyl, methylbenzyl,            t.-butylbenzyl, methoxybenzyl, dimethoxybenzyl,            fluorobenzyl, difluorobenzyl, trifluoromethylbenzyl,            trifluoromethoxybenzyl, chlorobenzyl, aminobenzyl,            nitrobenzyl, methoxycarbonylbenzyl, methylsulfonylbenzyl,            phenethyl, phenpropyl),        -   a heterocyclic-alkyl group, which is saturated, partially            saturated or fully unsaturated, having 5 to 10 ring atoms in            which at least 1 ring atom is an N, O or S atom, which is            unsubstituted or substituted one or more times in the            heterocyclic portion by halogen, alkyl, hydroxy, alkoxy,            halogenated alkyl (e.g., trifluoromethyl), halogenated            alkoxy, nitro, methylenedioxy, ethylenedioxy, amino,            alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy,            carboxy, cyano, acyl, alkoxycarbonyl, alkylthio,            alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl,            phenyl, halogenated phenyl, phenoxy, acyloxy, tetrazolyl,            alkylsulphonimide, arylsulphonimide, aryl, oxo, or            combinations thereof and/or substituted in the alkyl portion            by halogen, oxo, cyano, or combinations thereof (e.g.,            pyridylmethyl),        -   cycloalkylalkyl having 4 to 16 carbon atoms (e.g.,            cyclopentylethyl and cyclopropylmethyl), which is            unsubstituted or substituted one or more times by halogen,            oxo, alkyl or combinations thereof, or alkoxyalkyl having 3            to 8 carbon atoms;    -   R⁴ is alkyl having 1 to 6 carbon atoms, which is unsubstituted        or substituted one or more times by halogen, oxo, or        combinations thereof wherein optionally one or more —CH₂CH₂—        groups are replaced in each case by —CH═CH— or —C≡C— groups        (e.g., CH₃);    -   R⁵ is H, or        -   alkyl having 1 to 6 carbon atoms, which is unsubstituted or            substituted one or more times by halogen wherein optionally            one or more —CH₂CH₂— groups are replaced in each case by            —CH═CH— or —C≡C— groups (e.g., CH₃, C₂H₅);    -   R⁶ is H,        -   alkyl having 1 to 6 carbon atoms, which is unsubstituted or            substituted one or more times by halogen, oxo, hydroxy or            combinations thereof wherein optionally one or more —CH₂CH₂—            groups are replaced in each case by —CH═CH— or —C≡C— groups,        -   alkoxyalkyl having 2 to 6 carbon atoms (e.g., methoxyethyl            (CH₂CH₂OCH₃), ethoxymethyl (CH₂OCH₂CH₃)), which is            unsubstituted or substituted one or more times by halogen,            oxo, or combinations thereof;        -   alkoxycarbonyl (—C(═O)O-alkyl) having 2 to 6 carbon atoms            (e.g., —C(═O)OCH(CH₃)₂);        -   —CO—NR⁵R¹²;        -   cycloalkyl having 3 to 8 carbon atoms, which is            unsubstituted or substituted one or more times by halogen,            oxo, alkyl, or combinations thereof (e.g., cyclopentyl),        -   cycloalkylalkyl having 4 to 16 carbon atoms (e.g.,            cyclopentylethyl and cyclopropylmethyl), which is            unsubstituted or substituted one or more times by halogen,            oxo, alkyl or combinations thereof,        -   aryl having 6 to 14 carbon atoms, which is unsubstituted or            substituted one or more times by halogen, CF₃, OCF₃, alkyl,            hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy,            amino, alkylamino, dialkylamino, hydroxyalkyl,            hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl,            alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido            (e.g., acetamido), and acyloxy (e.g., acetoxy), or            combinations thereof,        -   arylalkyl having 7 to 16 carbon atoms, which is            unsubstituted or substituted, preferably in the aryl            portion, one or more times by halogen, CF₃, OCF₃, alkyl,            hydroxy, alkoxy, nitro, methylenedioxy, ethylenedioxy,            amino, alkylamino, dialkylamino, hydroxyalkyl,            hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl,            alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido            (e.g., acetamido), and acyloxy (e.g., acetoxy), or            combinations thereof,        -   a heterocyclic group, which is saturated, partially            saturated or fully unsaturated, having 5 to 10 ring atoms in            which at least 1 ring atom is an N, O or S atom (e.g.,            3-thienyl, 2-thienyl, 3-tetrahydrofuranyl, 2-pyrimidinyl,            4-tetrahydropyranyl), which is unsubstituted or substituted            one or more times by halogen, aryl, alkyl, alkoxy,            alkoxycarbonyl, cyano, halogenated alkyl (e.g.,            trifluoromethyl), nitro, oxo, amino, alkylamino,            dialkylamino, or combinations thereof, or        -   a heterocyclic-alkyl group, which is saturated, partially            saturated or fully unsaturated, having 5 to 10 ring atoms in            which at least 1 ring atom is an N, O or S atom, which is            unsubstituted or substituted one or more times in the            heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano,            halogenated alkyl (e.g., trifluoromethyl), nitro, oxo,            amino, alkylamino, dialkylamino, carboxy or combinations            thereof and/or substituted in the alkyl portion by halogen,            oxo, cyano, or combinations thereof;    -   R⁷ is H, halogen, or alkyl having 1 to 6 carbon atoms wherein        optionally one or more —CH₂CH₂— groups are replaced in each case        by —CH═CH— or —C≡C— groups and wherein the alkyl is        unsubstituted or substituted one or more times by halogen;    -   R⁸ is H, halogen, alkyl having 1 to 6 carbon atoms wherein        optionally one or more —CH₂CH₂— groups are replaced in each case        by —CH═CH— or —C≡C— groups and wherein the alkyl is        unsubstituted or substituted one or more times by halogen or        hydroxyl (e.g., CH₃, C₂H₅, CF₃, hydroxymethyl,        2-(2-hydroxy)propyl, hydroxymethyl), carboxy, alkoxycarbonyl        having 2 to 6 carbon atoms (e.g., ethoxycarbonyl), —CO-alkyl        having 2 to 6 carbon atoms (e.g., CH₃CO), or phenyl;    -   R⁹ is halogen (e.g., F); and    -   R¹⁰ is H,        -   alkyl having 1 to 8 carbon atoms, which is unsubstituted or            substituted one or more times by halogen, oxo or            combinations thereof wherein optionally one or more —CH₂CH₂—            groups are replaced in each case by —CH═CH— or —C≡C— groups            (e.g., CH₃, CHF₂), or        -   alkoxy having 2 to 8 carbon atoms, which is unsubstituted or            substituted one or more times by halogen;    -   R¹¹ is H,        -   alkyl having 1 to 6 carbon atoms (e.g., methyl,            ethylpropyl), which is unsubstituted or substituted one or            more times by halogen, oxo, or combinations thereof wherein            optionally one or more —CH₂CH₂— groups are replaced in each            case by —CH═CH— or —C≡C— groups (e.g., CH₃, C₂H₅), or        -   a heterocyclic-alkyl group, which is saturated, partially            saturated or fully unsaturated, having 5 to 10 ring atoms in            which at least 1 ring atom is an N, O or S atom, which is            unsubstituted or substituted one or more times in the            heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano,            halogenated alkyl (e.g., trifluoromethyl), nitro, oxo,            amino, alkylamino, dialkylamino, carboxy or combinations            thereof and/or substituted in the alkyl portion by halogen,            oxo, cyano, or combinations thereof (e.g.,            tetrahydro-2H-pyranylmethyl, pyrollidinylethyl;    -   R¹² is H,        -   alkyl having 1 to 6 carbon atoms (e.g., methyl,            ethylpropyl), which is unsubstituted or substituted one or            more times by halogen, oxo, or combinations thereof wherein            optionally one or more —CH₂CH₂— groups are replaced in each            case by —CH═CH— or —C≡C— groups (e.g., CH₃, C₂H₅),        -   cycloalkyl having 3 to 8 carbon atoms, which is            unsubstituted or substituted one or more times by halogen,            oxo, alkyl, or combinations thereof (e.g., cyclopentyl), or        -   a heterocyclic-alkyl group, which is saturated, partially            saturated or fully unsaturated, having 5 to 10 ring atoms in            which at least 1 ring atom is an N, O or S atom, which is            unsubstituted or substituted one or more times in the            heterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano,            halogenated alkyl (e.g., trifluoromethyl), nitro, oxo,            amino, alkylamino, dialkylamino, carboxy or combinations            thereof and/or substituted in the alkyl portion by halogen,            oxo, cyano, or combinations thereof (e.g., furylmethyl);

and pharmaceutically acceptable salts or solvates (e.g., hydrates)thereof, or solvates of pharmaceutically acceptable salts thereof.

According to a further method aspect of the invention, the compounds areof formulas I, II, III, IV, V, VI, VII or VIII, wherein L is(CH₂)_(n)OCONH, particularly compounds of formula IV wherein L is(CH₂)_(n)OCONH.

According to a further method aspect of the invention, the compounds areof formulas I, II, III, IV, V, VI, VII or VIII, particularly IV and VI,wherein R³ is aryl having 6 to 14 carbon atoms (particularly phenyl orbiphenyl), which is substituted by at least one substituent selectedfrom —CO—N(R¹⁰)₂ (wherein R¹⁰ is preferably, H, alkyl or alkoxy),aminosulfonyl, furanyl which is unsubstituted or substituted by halogen,C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl and/or benzyl, pyrrolylwhich is unsubstituted or substituted by halogen, C₁₋₄-alkyl,C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl, pyrazolyl which issubstituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl,and/or benzyl, isoxazolyl which is unsubstituted or substituted byhalogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl,imidazolyl which is substituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy,C₂₋₈-alkoxycarbonyl, and/or benzyl, pyridinyl which is substituted byhalogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl,pyrimidinyl which is unsubstituted or substituted by halogen,C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl, morpholinylwhich is substituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or benzyl,piperadinyl which is substituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl,and/or benzyl, piperazinyl which is substituted by C₁₋₄-alkyl,C₂₋₈-alkoxycarbonyl, and/or benzyl, tetrazolyl which is unsubstituted orsubstituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or benzyl, orarylsulphonimide (e.g., C₆H₅SO₂—NHCO—) wherein the aryl portion issubstituted by halogen or C₁₋₄-alkoxy.

According to a further method aspect of the invention, the compounds areof Formula IX or X, e.g., Formula IX.

According to a further method aspect of the invention, the compounds areof formulas I, II, III, IV, V, VI, VII or VIII, particularly IV and VI,wherein R³ is aryl substituted at least once by —SO₂—N(R¹⁰)₂,alkoxyalkoxy (e.g., methoxyethoxy), alkoxyalkoxyalkyl (e.g.,CH₃OCH₂CH₂OCH₂—) or benzyloxy.

According to a further method aspect of the invention, the compounds areof formulas III or VI, wherein R⁶ is alkyl having 1 to 6 carbon atomswhich is substituted at least once by hydroxy; alkoxyalkyl having 2 to 6carbon atoms (e.g., methoxyethyl, ethoxymethyl), which is unsubstitutedor substituted one or more times by halogen, oxo, or combinationsthereof; alkoxycarbonyl (—C(═O)O-alkyl) having 2 to 6 carbon atoms(e.g., —C(═O)OCH(CH₃)₂); or —CONR⁵—R¹².

The compounds of the present invention are effective in inhibiting, ormodulating the activity of PDE4 in animals, e.g., mammals, especiallyhumans. These compounds exhibit neurological activity, especially wheresuch activity affects cognition, including long term memory. Thesecompounds will also be effective in treating diseases where decreasedcAMP levels are involved. This includes, but is not limited to,inflammatory diseases. These compounds may also function asantidepressants, or be useful in treating cognitive and negativesymptoms of schizophrenia.

Assays for determining PDE4 inhibiting activity, selectivity of PDE4inhibiting activity, and selectivity of inhibiting PDE4 isoenzymes areknown within the art. See, e.g., U.S. Pat. No. 6,136,821, the disclosureof which is incorporated herein by reference.

Halogen herein refers to F, Cl, Br, and I. Preferred halogens are F andCl.

Alkyl means a straight-chain or branched-chain aliphatic hydrocarbonradical. Suitable alkyl groups include, but are not limited to, methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. Other examples ofsuitable alkyl groups include 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-,1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,ethylmethylpropyl, trimethylpropyl, methylhexyl, dimethylpentyl,ethylpentyl, ethylmethylbutyl, dimethylbutyl, and the like.

These alkyl radicals can optionally have one or more —CH₂CH₂— groupsreplaced in each case by —CH═CH— or —C≡C— groups. Suitable alkenyl oralkynyl groups are 1-propenyl, 2-propenyl, 1-propynyl, 1-butenyl,2-butenyl, 3-butenyl, 1-butynyl, 1,3-butadienyl, and 3-methyl-2-butenyl.

In the arylalkyl groups, heterocyclic-alkyl groups, cycloalkyl-alkylgroups and alkoxyalkyl groups, “alkyl” refers to a divalent alkylenegroup having in general up to about 13 carbon atoms. In the case of thearylalkyl group, the “alkyl” portion has, for example, up to 10 carbonatoms, preferably 1 to 6 carbon atoms. In the heterocyclic-alkyl groups,the “alkyl” portion has, for example, 1 to 12 carbon atoms, preferably 1to 4 carbon atoms. In the alkoxyalkyl groups, the “alkyl” portionpreferably has 2 to 7 carbon atoms. In the cycloalkylalkyl groups, the“alkyl” portion has, for example, 1 to 13 carbon atoms, preferably 1 to4 carbon atoms.

In the cases where alkyl is a substituent (e.g., alkyl substituents onaryl and heterocyclic groups) or is part of a substituent (e.g., in thealkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, alkylthio,alkylsulfinyl, and alkylsulfonyl substituents for aryl), the alkylportion preferably has 1 to 12 carbon atoms, especially 1 to 8 carbonatoms, in particular 1 to 4 carbon atoms.

Alkoxy means alkyl-O— groups in which the alkyl portion has 1 to 8carbon atoms, and which can be substituted, for example, by halogens.Suitable alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy,isobutoxy, sec-butoxy, pentoxy, hexoxy, heptoxy, octoxy, andtrifuoromethoxy. Preferred alkoxy groups are methoxy, ethoxy anddifluoromethoxy.

Similarly, alkoxycarbonyl means an alkyl-O—CO— group in which the alkylportion has 1 to 8 carbon atoms, e.g., 2 to 6 carbon atoms.

Alkoxyalkoxy means alkyl-O-alkyl-O— groups in which each of the alkylportions have 1 to 8 carbon atoms (e.g., 1 to 4 carbon atoms), and whichcan be substituted, for example, by halogens. Suitable alkoxyalkoxygroups include methoxyethoxy, ethoxymethoxy, propoxymethoxy, andisopropoxymethoxy.

Alkoxyalkoxyalkyl means alkyl-O-alkyl-O-alkyl-groups in which each ofthe alkyl portions have 1 to 8 carbon atoms (e.g., 1 to 4 carbon atoms),and which can be substituted, for example, by halogens. Suitablealkylalkoxyalkoxy groups include CH₃OCH₂CH₂OCH₂—.

Alkenyl refers to straight-chain or branched-chain aliphatic radicalscontaining 2 to 12 carbon atoms in which one or more —CH₂—CH₂—structures is replaced by —CH═CH—. Suitable alkenyl groups are ethenyl,1-propenyl, 2-methylethenyl, 1-butene, 2-butene, 1-pentenyl, and2-pentenyl. In the arylalkenyl groups, alkenyl refers to an alkyenylenegroup having preferably 2 to 5 carbon atoms.

Cycloalkyl means a monocyclic, bicyclic or tricyclic saturatedhydrocarbon radical having 3 to 8 carbon atoms, preferably 4 to 6 carbonatoms, more preferably 5 carbon atoms. Suitable cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and norbornyl. Other suitable cycloalkyl groups includespiropentyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl,spiro[2.4]heptyl, spiro[2.5]octyl, bicyclo[5.1.0]octyl, spiro[2.6]nonyl,bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, and bicyclo[4.2.0]octyl.

The cycloalkyl group can be substituted by halogens, oxo and/or alkyl.

Cycloalkylalkyl refers to a cycloalkyl-alkyl-radical in which thecycloalkyl and alkyl portions are in accordance with the previousdescriptions. Suitable examples include cyclopentylethyl andcyclopropylmethyl.

Aryl, as a group or substituent per se or as part of a group orsubstituent, refers to an aromatic carbocyclic radical containing 6 to14 carbon atoms, preferably 6 to 12 carbon atoms. Suitable aryl groupsinclude phenyl, naphthyl and biphenyl. Substituted aryl groups include,but are not limited to, the above-described aryl groups which aresubstituted one or more times by halogen, alkyl, hydroxy, alkoxy, nitro,methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino,hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl,alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy, and acyloxy (e.g.,acetoxy).

Arylalkyl refers to an aryl-alkyl-radical in which the aryl and alkylportions are in accordance with the previous descriptions. Suitableexamples include 1-phenethyl, 2-phenethyl, phenpropyl, phenbutyl,phenpentyl, and naphthylenemethyl.

Arylalkenyl refers to an aryl-alkenyl-radical in which the aryl andalkenyl portions are in accordance with the previous descriptions ofaryl and alkenyl. Suitable examples include 3-aryl-2-propenyl.

Heterocyclic groups refer to saturated, partially saturated and fullyunsaturated heterocyclic groups having one or two rings and a totalnumber of 5 to 10 ring atoms wherein at least one of the ring atoms isan N, O or S atom. Preferably, the heterocyclic group contains 1 to 3,especially 1 or 2, hetero-ring atoms selected from N, O and S. Suitablesaturated and partially saturated heterocyclic groups include, but arenot limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl,isoxazolinyl, thiazolyl and the like. Suitable heteroaryl groups includebut are not limited to furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,pyridyl, pyrimidinyl, indolyl, quinolinyl, naphthyridinyl, azaindolyl(e.g.,7-azaindolyl), 1,2,3,4, -tetrahydroisoquinolyl, and the like.Preferred heterocyclic and heteroaryl groups include terahydrofuranyl,tetrahydropyranyl, 2-thienyl, 3-thienyl, 2-, 3- or 4-pyridyl, 2-, 3-,4-, 5-, 6-, 7- or 8-quinolin and 1-, 3-, 4-, 5-, 6-, 7- or8-isoquinolinyl.

Substituted heterocyclic groups refer to the heterocyclic groupsdescribed above which are substituted in one or more places by, forexample, halogen, aryl, alkyl, alkoxy, cyano, halogenated alkyl (e.g.,trifluoromethyl), nitro, oxo, amino, alkylamino, and dialkylamino.

Heterocyclic-alkyl refers to a heterocyclic-alkyl-group wherein theheterocyclic and alkyl portions are in accordance with the previousdiscussions. Suitable examples are pyridylmethyl, thienylmethyl,pyrimidinylmethyl, pyrazinylmethyl, isoquinolinylmethyl, pyridylethyland thienylethyl.

Partially unsaturated carbocyclic structures are non-aromatic monocyclicor bicyclic structures containing 5 to 14 carbon atoms, preferably 6 to10 carbon atoms, wherein the ring structure(s) contains at least one C═Cbond. Suitable examples are cyclopentenyl, cyclohexenyl,tetrahydronaphthenyl and indan-2-yl.

Acyl refers to alkanoyl radicals having 1 to 13 carbon atoms in whichthe alkyl portion can be substituted by halogen, hydroxy, carboxy,alkyl, aryl and/or alkoxy; or aroyl radicals having 7 to 15 carbon atomsin which the aryl portion can be substituted by halogen, alkyl, alkoxy,nitro, carboxy and/or hydroxy. Suitable acyl groups include formyl,acetyl, propionyl, butanoyl and benzoyl.

Substituted radicals preferably have 1 to 3 substituents, especially 1or 2 substituents.

In each case, X is preferably CH and L is preferably a single bond.

R¹ is preferably alkyl having 1 to 2 carbon atoms, which isunsubstituted or substituted, and more preferably 1 carbon atom. For R¹,the substituted alkyl groups are preferably substituted one or moretimes by halogen, especially F and Cl. More preferably, R¹ is CH₃ orCF₂H.

R² is preferably alkyl having 1 to 4 carbon atoms. For R², thesubstituted alkyl groups are preferably substituted one or more times byhalogen, especially F and Cl. Preferably, R² is alkyl having 1 to 4carbons which is unsubstituted or substituted with one or more F atoms.

R² can also be preferably cycloalkylalkyl group, wherein the “alkyl”portion preferably has 1 to 2 carbon atoms. R² is also preferably acycloalkyl, which has 4 to 7 atoms. R² is also preferably a saturatedheterocyclic group with 5 to 7 atoms and containing 1 or 2 hetero-ringatoms selected from O and S. More preferably, R² is a saturatedheterocyclic group with 5 ring atoms containing 1 hetero-ring atomselected from O and S.

In particular, R² is preferably alkyl, halogenated alkyl, cycloalkylwhich is substituted or unsubstituted, cycloalkylalkyl which issubstituted or unsubstituted, tetrahydrofuranyl, or arylalkyl which issubstituted or unsubstituted. More preferably, R₂ is CH₃, C₂H₅,isopropyl, CF₂H, cyclobutyl, cyclopentyl, cyclopropylmethyl, or3-tetrahydrofuranyl.

R³ is preferably aryl preferably having 6 to 14 carbon atoms(particularly phenyl or biphenyl) which is unsubstituted or substitutedwith one or more halogen (preferably fluorine), cyano, nitro, amino,alkyl (preferably methyl), alkoxy (preferably methoxy) or carboxy (e.g.,phenyl, bromophenyl, nitrophenyl, fluorophenyl, methoxyphenyl,carboxyphenyl, trifluoromethoxyphenyl, dimethylphenyl, 4-carboxyphenyl,2,3-difluorophenyl, 4-methylphenyl, 4-tert.-butylphenyl,4-methoxyphenyl, 3,4-difluorophenyl, or 4-fluorophenyl). R³ is alsopreferably an aryl having 6 to 14 carbon atoms (particularly phenyl orbiphenyl), which is substituted by at least one substituent selectedfrom —CO—N(R¹⁰)₂ (wherein R¹⁰ is preferably, H, alkyl or alkoxy),aminosulfonyl, furanyl which is unsubstituted or substituted by halogen,C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl and/or benzyl, pyrrolylwhich is unsubstituted or substituted by halogen, C₁₋₄-alkyl,C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl, pyrazolyl which issubstituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl,and/or benzyl, isoxazolyl which is unsubstituted or substituted byhalogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl,imidazolyl which is substituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy,C₂₋₈-alkoxycarbonyl, and/or benzyl, pyridinyl which is substituted byhalogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl,pyrimidinyl which is unsubstituted or substituted by halogen,C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl, morpholinylwhich is substituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or benzyl,piperadinyl which is substituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl,and/or benzyl, piperazinyl which is substituted by C₁₋₄-alkyl,C₂₋₈-alkoxycarbonyl, and/or benzyl, tetrazolyl which is unsubstituted orsubstituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or benzyl, orarylsulphonimide (e.g., C₆H₅SO₂—NHCO—) wherein the aryl portion issubstituted by halogen or C₁₋₄-alkoxy.

R³ can also preferably be a cycloalkyl group, and more preferablycyclohexyl or cyclopentyl. R³ can also preferably be an alkyl group,more preferably ethyl, CH(CH₃)₂, n-propyl, n-butyl, or t-butyl.

R³ is also preferably a heterocyclic group, more preferably thiazolyl,pyridyl or benzothiazolyl, which in each case is substituted orunsubstituted.

In accordance with a further preference, R³ is arylalkyl such as benzylor phenethyl, which in each case is substituted or unsubstituted. Inparticular, R³ is an arylalkyl selected from benzyl, methylbenzyl,t.-butylbenzyl, methoxybenzyl, dimethoxybenzyl, carboxybenzyl,fluorobenzyl, difluorobenzyl, trifluoromethylbenzyl,trifluoromethoxybenzyl, chlorobenzyl, nitrobenzyl,methoxycarbonylbenzyl, and phenethyl.

In accordance with a further preference, R³ is a heterocyclic-alkylgroup, which is saturated, partially saturated or fully unsaturated,having 5 to 10 ring atoms in which at least 1 ring atom is an N, O or Satom, and which is optionally substituted one or more times in theheterocyclic portion by, for example, halogen, alkyl, hydroxy, alkoxy,halogenated alkyl (e.g., trifluoromethyl), halogenated alkoxy, nitro,amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy,cyano, or combinations thereof and/or optionally substituted in thealkyl portion by halogen, oxo, cyano, or combinations thereof (e.g.,pyridylmethyl).

Overall, for each formula, R³ is preferably ethyl, aryl (e.g., phenyl)or heteroaryl, and L is preferably a single bond.

R⁴ is preferably alkyl having 1 to 3 carbon atoms, and more preferablyR⁴ is CH₃. R⁴ is preferably a substituted alkyl group having 1 to 3carbon atoms and is preferably substituted one or more times by halogen,especially F and Cl.

When R⁵ is a substituent on the indazole or pyrazolo-pyridine ring (seeformulas III, VI and IX), then it is preferably alkyl having 1 to 3carbon atoms. More preferably, R⁵is CH₃ or CH₂CH₃.

When R⁵ is part of the —COR⁵R¹² group (see the definition of R⁶), thenit is preferably H.

R⁶ is preferably other than H. For example, R⁶ is preferably cycloalkylhaving 4 to 7 carbon atoms, and more preferably is cyclopropyl orcyclopentyl.

R⁷ and R⁸ are each preferably H. R⁸ can also preferably be alkyl,fluorinated alkyl, hydroxyalkyl, carboxy, alkoxycarbonyl having 2 to 6carbon atoms (e.g., ethoxycarbonyl), —CO-alkyl having 2 to 6 carbonatoms (e.g., CH₃CO), or phenyl. For example, R⁸ can be H, CH₃, C₂H₅,CF₃, hydroxymethyl, 2-(2-hydroxy)propyl), carboxy, ethoxycarbonyl,CH₃CO, or phenyl.

R⁹ preferably is F.

R¹⁰ preferably is H or alkyl having 1 to 8 carbon atoms (e.g., 1 to 4carbon atoms), such as methyl, ethyl, isopropyl.

R¹¹ preferably is alkyl having 1 to 6 carbon atoms (e.g., methyl, ethyl,ethylpropyl) or heterocyclic-alkyl group (e.g.,tetrahydro-2H-pyranylmethyl, pyrrolidinylethyl).

R¹² preferably is alkyl having 1 to 6 carbon atoms (e.g., methyl, ethyl,ethylpropyl) or heterocyclic-alkyl group (e.g., furylmethyl).

X is preferably CH.

L is preferably a bond, CH₂, CH₂CH₂, CH₂CO, CH₂CO₂, or CH₂CONH. L isalso preferably (CH₂)_(n)OCONH.

The subscript n is preferably 0 or 2.

Preferred compounds of the invention are those of Formulas III, IV, andVI, partriculaly those of Formulas IV and VI, especially those ofFormula VI.

In addition, preferred PDE4 inhibitors in accordance with the inventionare compounds described by subformulas Ia-Im, IIa-IIIy, IVa-IVm, Va-Vh,VIa-VIy, VIIa-VIIe, VIIIa-VIIIe, IXa-IXf and Xa-Xf which correspond toFormulas I, II, III, IV, V, VI, VII, VIII, IX or X but exhibit thefollowing preferred groups:

-   -   Ia or IVa        -   R¹ is CH₃ or CF₂H.    -   Ib or IVb        -   R¹ is CH₃ or CF₂H; and        -   R² is alkyl, cycloalkyl, cycloalkylalkyl, or a heterocyclic            group, which in each case is substituted or unsubstituted.    -   Ic or IVc        -   R¹ is CH₃ or CF₂H; and        -   R² is CF₂H, cyclopropylmethyl, or 3-tetrahydrofuranyl            (preferably 3-(3R)-tetrahydrofuranyl).    -   Id or IVd        -   R¹ is CH₃ or CF₂H; and        -   R³ is alkyl, cycloalkyl, aryl, arylalkyl, heterocyclic            group, or heterocyclic-alkyl group, which in each case is            substituted or unsubstituted.    -   Ie or IVe        -   R¹ is CH₃ or CF₂H;        -   R³ is alkyl, cycloalkyl, aryl, arylalkyl, heterocyclic            group, or heterocyclic-alkyl group; and        -   L is a bond, CH₂, CH₂CH₂, or (CH₂)_(n)OCONH (e.g.,            CH₂CH₂OCONH).    -   If or IVf        -   R¹ is CH₃ or CF₂H;        -   R² is alkyl, cycloalkyl, cycloalkylalkyl, or a heterocyclic            group, which in each case is substituted or unsubstituted;        -   R³ is alkyl, cycloalkyl, aryl, arylalkyl, heterocyclic            group, or heterocyclic-alkyl group, which in each case is            substituted or unsubstituted; and        -   L is a bond, CH₂, or (CH₂)_(n)OCONH (e.g., CH₂CH₂OCONH).    -   Ig or IVg        -   R¹ is CH₃ or CF₂H;        -   R² is CF₂H, cyclopropylmethyl, or 3-tetrahydrofuranyl            (preferably 3-(3R)-tetrahydrofuranyl);        -   R³ is alkyl, cycloalkyl, aryl, arylalkyl, heterocyclic            group, or heterocyclic-alkyl group, which in each case is            substituted or unsubstituted; and        -   L is a bond, CH₂, CH₂CH₂, or (CH₂)_(n)OCONH (e.g.,            CH₂CH₂OCONH).    -   Ih or IVh        -   R³ is aryl (e.g., phenyl or biphenyl), arylalkyl (e.g.,            benzyl), or heterocyclic group (e.g., pyridinyl, thiazinyl,            or piperidinyl), which in each case is substituted or            unsubstituted; and        -   L is a bond.    -   Ii or IVi R³ is phenyl, biphenyl, or benzyl which is        unsubstituted or substituted by at least one substituent        selected from alkyl, alkoxy, halogenated alkoxy, halogen (e.g.,        F), carboxy, amino, cyano, alkylsulfonyl, acyl (e.g., acetyl),        aminosulfonyl, —CO—N(R¹⁰)₂, acylamido (e.g., acetamido),        alkylsulphonimide, arylsulphonimide (e.g., C₆H₅SO₂—NHCO—)        wherein the aryl portion is optionally substituted by halogen or        C₁₋₄-alkoxy, furanyl which is unsubstituted or substituted by        halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl and/or        benzyl, pyrrolyl which is unsubstituted or substituted by        halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or        benzyl, pyrazolyl which is substituted by halogen, C₁₋₄-alkyl,        C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl, isoxazolyl        which is unsubstituted or substituted by halogen, C₁₋₄-alkyl,        C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl, imidazolyl        which is substituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy,        C₂₋₈-alkoxycarbonyl, and/or benzyl, pyridinyl which is        substituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy,        C₂₋₈-alkoxycarbonyl, and/or benzyl, pyrimidinyl which is        unsubstituted or substituted by halogen, C₁₋₄-alkyl,        C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl, morpholinyl        which is substituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or        benzyl, piperadinyl which is substituted by C₁₋₄-alkyl,        C₂₋₈-alkoxycarbonyl, and/or benzyl, piperazinyl which is        substituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or benzyl,        tetrazolyl which is unsubstituted or substituted by C₁₋₄-alkyl,        C₂₋₈-alkoxycarbonyl, and/or benzyl; and        -   L is a bond.    -   Ij or IVj        -   R³ is alkyl, cycloalkyl, aryl (e.g., phenyl), arylalkyl            (e.g., benzyl), heterocyclic group, or heterocyclic-alkyl            group (e.g., thienyl), which in each case is substituted or            unsubstituted; and        -   L is (CH₂)_(n)OCONH.    -   Ik or IVk        -   R³ is alkyl, cyclopentyl, phenyl which is unsubstituted or            substituted by alkyl, alkoxy, halogen, or cyano), benzyl),            thienyl, isoxazolyl which is unsubstituted or substituted by            alkyl (e.g., dimethylisoxazolyl), furanylmethyl, or            heterocyclic-alkyl group (e.g., pyridinyl, thiazinyl, or            piperidinyl), which in each case is substituted or            unsubstituted; and        -   L is (CH₂)_(n)OCONH.    -   Im or IVm        -   R¹ is methyl or difluoromethyl;        -   R² is difluoromethyl, methyl, ethyl, terathydrofuranyl,            cyclopentyl, or cyclopropyl; and        -   R⁷ and R⁸ are each H.    -   IIIa or VIa R⁵ is alkyl having 1 to 3 carbon atoms (e.g.,        ethyl).    -   IIIb or VIb R⁶ is cycloalkyl having 4 to 7 carbon atoms (e.g.,        cyclopentyl).    -   IIIc or VIc R⁶ is cycloalkyl having 3 to 7 carbon atoms (e.g.,        cyclopropyl or cyclopentyl).    -   IIId or VId R⁶ is cycloalkyl having 3 to 7 carbon atoms (e.g.,        cyclopropyl or cyclopentyl), alkyl having 1 to 6 carbon atoms        (e.g., isopropyl), or a heterocyclic group (e.g.,        4-tetrahydropyranyl, 2-pyrimdinyl, or 3-tetrahydrofuranyl).    -   IIIe or VIe R³ is aryl (e.g., phenyl), arylalkyl (e.g., benzyl),        or heteroaryl group (e.g., pyridinyl, pyrimidinyl, pyrazolyl, or        pyrrolyl), which in each case is substituted or unsubstituted.    -   IIIf or VIf R⁵ is ethyl; and        -   R⁶ is isopropyl, cyclopropyl, cyclopentyl,            4-tetrahydropyranyl, or 2-pyrimidinyl.    -   IIIg or VIg R⁵ is alkyl having 1 to 3 carbon atoms (e.g.,        ethyl);        -   R⁶ is cycloalkyl having 4 to 7 carbon atoms (e.g.,            cyclopentyl); and        -   R³ is aryl (e.g., phenyl), arylalkyl (e.g., benzyl), or            heteroaryl group (e.g., pyridinyl, pyrimidinyl, pyrazolyl,            or pyrrolyl), which in each case is substituted or            unsubstituted.    -   IIIh or VIh R⁵ is alkyl having 1 to 3 carbon atoms (e.g.,        ethyl);        -   R⁶ is cycloalkyl having 3 to 7 carbon atoms (e.g.,            cyclopropyl or cyclopentyl); and        -   R³ is aryl (e.g., phenyl), arylalkyl (e.g., benzyl), or            heteroaryl group (e.g., pyridinyl, pyrimidinyl, pyrazolyl,            or pyrrolyl), which in each case is substituted or            unsubstituted.    -   IIIi or VIi R⁵ is alkyl having 1 to 3 carbon atoms (e.g.,        ethyl);        -   R⁶ is cycloalkyl having 3 to 7 carbon atoms (e.g.,            cyclopropyl or cyclopentyl), alkyl having 1 to 6 carbon            atoms (e.g., isopropyl), or a heterocyclic group (e.g.,            4-tetrahydropyranyl, 2-pyrimidinyl, or 3-tetrahydrofuranyl);            and        -   R³ is aryl (e.g., phenyl), arylalkyl (e.g., benzyl), or            heteroaryl group (e.g., pyridinyl, pyrimidinyl, pyrazolyl,            or pyrrolyl), which in each case is substituted or            unsubstituted.    -   IIIj or VIj R⁵ is alkyl having 1 to 3 carbon atoms (e.g.,        ethyl);        -   R⁶ is cycloalkyl having 3 to 7 carbon atoms (e.g.,            cyclopropyl or cyclopentyl), alkyl having 1 to 6 carbon            atoms (e.g., isopropyl), or a heterocyclic group (e.g.,            4-tetrahydropyranyl, 2-pyrimidinyl, or 3-tetrahydrofuranyl);            and        -   R³ is aryl (e.g., phenyl, 4-methylsulfonylpenyl), alkyl            (e.g., ethyl), or heteroaryl group (e.g., pyridinyl,            pyrimidinyl, pyrazolyl, or pyrrolyl), which in each case is            substituted or unsubstituted.    -   IIIk or VIk L is a single bond.    -   IIIm or VIm R⁵ is alkyl having 1 to 3 carbon atoms (e.g.,        ethyl);        -   R⁶ is cycloalkyl having 3 to 7 carbon atoms (e.g.,            cyclopropyl or cyclopentyl);        -   R³ is aryl (e.g., phenyl), arylalkyl (e.g., benzyl), or            heteroaryl group (e.g., pyridinyl, pyrimidinyl, pyrazolyl,            or pyrrolyl), which in each case is substituted or            unsubstituted; and        -   L is a single bond.    -   IIIn or VIn R⁵ is CH₂CH₃;        -   R⁶ is cyclopentyl; and        -   R³ is aryl (e.g., phenyl), arylalkyl (e.g., benzyl), or            heteroaryl group (e.g., pyridinyl, pyrimidinyl, pyrazolyl,            or pyrrolyl), which in each case is substituted or            unsubstituted.    -   IIIo or VIo R⁵ is CH₂CH₃;        -   R⁶ is cyclopentyl;        -   R³ is aryl (e.g., phenyl), arylalkyl (e.g., benzyl), or            heteroaryl group (e.g., pyridinyl, pyrimidinyl, pyrazolyl,            or pyrrolyl), which in each case is substituted or            unsubstituted; and        -   L is a single bond.    -   IIIp or VIp R⁵ is CH₂CH₃;        -   R⁶ is cyclopentyl; and        -   R³ is aryl (e.g., phenyl), arylalkyl (e.g., benzyl), or            heteroaryl group (e.g., pyridinyl, pyrimidinyl, pyrazolyl,            or pyrrolyl), which in each case is substituted or            unsubstituted by alkyl, alkoxy, halogenated alkoxy, carboxy,            acetyl, cyano, halogen, —CO—N(R¹⁰)₂, aminosulfonyl,            alkylsulfonyl, tetrazolyl, alkoxyalkoxy, alkoxyalkyl,            hydroxyalkyl, hydroxyalkoxy, or hydroxy.    -   IIIq or VIq R⁵ is CH₂CH₃;        -   R⁶ is cyclopentyl;        -   R³ is aryl (e.g., phenyl), arylalkyl (e.g., benzyl), or            heteroaryl group (e.g., pyridinyl, pyrimidinyl, pyrazolyl,            or pyrrolyl), which in each case is substituted or            unsubstituted by alkyl, alkoxy, halogenated alkoxy, carboxy,            acetyl, cyano, halogen, —CO—N(R¹⁰)₂, aminosulfonyl,            alkylsulfonyl, tetrazolyl, alkoxyalkoxy, alkoxyalkyl,            hydroxyalkyl, hydroxyalkoxy, or hydroxy; and        -   L is a single bond.    -   IIIr or VIr R⁵ is CH₂CH₃;        -   R⁵ is cyclopropyl, isopropyl, tetrahydropyranyl, or            pyrmidinyl; and        -   R³ is aryl (e.g., phenyl), arylalkyl (e.g., benzyl), or            heteroaryl group (e.g., pyridinyl, pyrimidinyl, pyrazolyl,            or pyrrolyl), which in each case is substituted or            unsubstituted.    -   IIIs or VIs R⁵ is CH₂CH₃;        -   R⁶ is cyclopropyl, isopropyl, tetrahydropyranyl, or            pyrmidinyl;        -   R³ is aryl (e.g., phenyl), arylalkyl (e.g., benzyl), or            heteroaryl group (e.g., pyridinyl, pyrimidinyl, pyrazolyl,            or pyrrolyl), which in each case is substituted or            unsubstituted; and        -   L is a single bond.    -   IIIt or VIt R⁵ is CH₂CH₃;        -   R⁶ is cyclopropyl, isopropyl, tetrahydropyranyl, or            pyrmidinyl; and        -   R³ is aryl (e.g., phenyl), arylalkyl (e.g., benzyl), or            heteroaryl group (e.g., pyridinyl, piperidinyl, pyrimidinyl,            pyrazolyl, or pyrrolyl), which in each case is substituted            or unsubstituted by alkyl, alkoxy, halogenated alkoxy,            carboxy, acetyl, cyano, halogen, —CO—N(R¹⁰)₂, aminosulfonyl,            alkylsulfonyl, tetrazolyl, alkoxyalkoxy, alkoxyalkyl,            hydroxyalkyl, hydroxyalkoxy, or hydroxy.    -   IIIu or VIu R⁵ is CH₂CH₃;        -   R⁶ is cyclopropyl, isopropyl, tetrahydropyranyl, or            pyrmidinyl;        -   R³ is aryl (e.g., phenyl), arylalkyl (e.g., benzyl), or            hetereoaryl group (e.g., pyridinyl, piperidinyl,            pyrimidinyl, pyrazolyl, or pyrrolyl), which in each case is            substituted or unsubstituted by alkyl, alkoxy, halogenated            alkoxy, carboxy, acetyl, cyano, halogen, —CO—N(R¹⁰)₂,            aminosulfonyl, alkylsulfonyl, tetrazolyl, alkoxyalkoxy,            alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, or hydroxy; and        -   L is a single bond.    -   IIIv or VIv R⁵ is CH₂CH₃;        -   R⁶ is cyclopropyl, cyclopentyl, isopropyl,            tetrahydropyranyl, or pyrmidinyl; and        -   R³ is phenyl which is substituted or unsubstituted.    -   IIIw or VIw R⁵ is CH₂CH₃;        -   R⁶ is cyclopropyl, cyclopentyl, isopropyl,            tetrahydropyranyl, or pyrmidinyl;        -   R³ is phenyl which is substituted or unsubstituted; and        -   L is a single bond.    -   IIIx or VIx R⁵ is CH₂CH₃;        -   R⁶ is cyclopropyl, cyclopentyl, isopropyl,            tetrahydropyranyl, or pyrmidinyl; and        -   R³ is phenyl which is substituted or unsubstituted.    -   IIIy or VIy R⁵ is CH₂CH₃;        -   R⁶ is cyclopropyl, cyclopentyl, isopropyl,            tetrahydropyranyl, or pyrmidinyl;        -   R³ is phenyl which is substituted or unsubstituted; and        -   L is a single bond.    -   VIIa or VIIIa R¹ is CH₃;        -   R² is F or Br; and        -   R³ is substituted or unsubstituted aryl or arylalkyl.    -   VIIb or VIIIb R¹ is CH₃;        -   R² is F or Br;        -   R³ is substituted or unsubstituted aryl or arylalkyl; and        -   L is a bond.    -   VIIc or VIIIc R¹ is CH₃;        -   X is CH;        -   R² is F or Br;        -   R³ is substituted or unsubstituted aryl or arylalkyl;        -   L is a bond; and        -   R⁷ and R⁸ are each H.    -   VIId or VIIId R¹ is CH₃;        -   X is CH;        -   R² is F or Br;        -   R³ is substituted or unsubstituted phenyl or benzyl;        -   L is a bond; and        -   R⁷ and R⁸ are each H.    -   VIIe or VIIIe R¹ is CH₃;        -   X is CH;        -   R² is F or Br;        -   R³ is substituted or unsubstituted phenyl or benzyl;        -   L is a bond;        -   R⁷ and R⁸ are each H; and        -   X is CH.    -   IXa or Xa R⁵ is alkyl having 1 to 3 carbon atoms (e.g., ethyl).    -   IXb or Xb R¹¹ is alkyl having 1 to 6 carbon atoms,        tetrahydro-2H-pyranylmethyl or pyrrolidinylethyl.    -   IXc or Xc R³ is aryl (e.g., phenyl), arylalkyl (e.g., benzyl),        or heterocyclic group (e.g., pyridinyl, piperidinyl,        pyrimidinyl, pyrazolyl, or pyrrolyl), which in each case is        substituted or unsubstituted.    -   IXd or Xd L is a single bond.    -   IXe or Xe R⁵ is alkyl having 1 to 3 carbon atoms (e.g., ethyl);        -   R¹¹ is alkyl having 1 to 6 carbon atoms,            tetrahydro-2H-pyranylmethyl or pyrrolidinylethyl;        -   R³ is aryl (e.g., phenyl), arylalkyl (e.g., benzyl), or            heterocyclic group (e.g., pyridinyl, piperidinyl,            pyrimidinyl, pyrazolyl, or pyrrolyl), which in each case is            substituted or unsubstituted; and        -   L is a single bond.    -   IXf or Xf R⁵ is CH₂CH₃;        -   R¹¹ is methyl, tetrahydro-2H-pyranylmethyl or            pyrrolidinylethyl;        -   R³ is phenyl which in each case is substituted or            unsubstituted; and        -   L is a single bond.

According to preferred compounds of the invention, 5-aryl-1-substitutedpyrazoles and 5-heteroaryl-1-substituted pyrazoles (e.g. Formulas IV, V,and VI) are generally preferred over 3-aryl-1-substituted pyrazoles and3-heteroaryl-1-substituted pyrazoles (e.g. Formulas I, II, and III).

According to a further preferred compound and/or method aspect of theinvention, the compounds of Formulas I, II, III, IV, V, VI, VII and VIIIare selected from:

-   1)    1-cyclopentyl-3-ethyl-6-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-1H-indazol,-   2)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzoic    acid,-   3)    1-cyclopentyl-3-ethyl-6-(1-pyridin-2-yl-1H-pyrazol-5-yl)-1H-indazole,-   4)    1-cyclopentyl-6-[1-(3,4-difluorophenyl)-1H-pyrazol-5-yl]-3-ethyl-1H-indazole,-   5) 6-(1-benzyl-1H-pyrazol-5-yl)-1-cyclopentyl-3-ethyl-1H-indazole,-   6)    1-cyclopentyl-3-ethyl-6-(1-pyridin-4-yl-1H-pyrazol-5-yl)-1H-indazole,-   7)    1-cyclopentyl-3-ethyl-6-(1-piperidin-4-yl-1H-pyrazol-5-yl)-1H-indazole,-   8)    1-cyclopentyl-3-ethyl-6-[1-(4-pyrimidin-5-ylphenyl)-1H-pyrazol-5-yl]-indazole,-   9)    1-cyclopentyl-3-ethyl-6-{1-[4-(1H-pyrazol-4-yl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   10)    1-cyclopentyl-3-ethyl-6-{1-[4-(1H-pyrrol-2-yl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   11)    1-cyclopentyl-3-ethyl-6-[1-(4-pyridin-3-ylphenyl)-1H-pyrazol-5-yl]-1H-indazole,-   12)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzamide,-   13)    1-cyclopentyl-3-ethyl-6-{1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   14)    1-cyclopentyl-3-ethyl-6-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-1H-indazole,-   15)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzonitrile,-   16)    6-[1-(4-chlorophenyl)-1H-pyrazol-5-yl]-1-cyclopentyl-3-ethyl-1H-indazole,-   17)    1-cyclopentyl-3-ethyl-6-[1-(4-methylphenyl)-1H-pyrazol-5-yl]-1H-indazole,-   18)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzenesulfonamide,-   19)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N-(methylsulfonyl)benzamide,-   20)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N-(ethylsulfonyl)benzamide,-   21)    1-cyclopentyl-3-ethyl-6-{1-[4-(1H-tetrazol-5-yl)phenyl]-1H-pyrazol-5}-1H-indazole,-   22)    1-cyclopentyl-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   23)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N-methoxy-N-methylbenzamide,-   24)    1-{4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenyl}ethanone,-   25)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N,N-diethylbenzamide,-   26)    1-cyclopentyl-6-{1-[4-(difluoromethoxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1H-indazole,-   27)    4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrzol-1-yl)phenyl]morpholine,-   28) 4-{[5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]methyl}benzoic    acid,-   29)    4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzoic    acid,-   30)    5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole,-   31)    2-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)-1,3-thiazole,-   32) 1-benzyl-5-(3,4-dimethoxyphenyl)-1H-pyrazole,-   33)    2-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzoic    acid,-   34)    3-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzoic    acid,-   35)    1-[4-(3-furyl)phenyl]-5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazole,-   36)    4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]-N-(phenylsulfonyl)benzamide,-   37)    N-[(4-methoxyphenyl)sulfonyl]-4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]benzamide,-   38)    N-[(4-fluorophenyl)sulfonyl]-4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]benzamide,-   39) tert-butyl    4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]piperazine-1-carboxylate,-   40) 4-[5-(3,4-dimethoxyphenyl)-1H-pyrazol-1-yl]pyridine,-   41)    4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)pyridine,-   42)    4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)piperidine,-   43)    1-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]piperazine,-   44)    1-(4-fluorobenzyl)-5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-4-methyl-1H-pyrazole,-   45) 5-(3-Bromo-4-methoxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazole,-   46)    5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1-[4-(1H-pyrrol-2-yl)phenyl]-1H-pyrazole,-   47)    3-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]pyridine,-   48)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(4-fluorophenyl)carbamate,-   49)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    benzylcarbamate,-   50)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    1-methylpropylcarbamate,-   51)    1-Isobutyl-5-(4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl)-1H-pyrazole,-   52)    5-[3,4-bis(difluoromethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazole,-   53)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    phenylcarbamate,-   54)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    propylcarbamate,-   55)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    (2-fluorophenyl)carbamate,-   56)    5-[4-(difluoromethoxy)-3-methoxyphenyl]-1-(4-methoxyphenyl)-1H-pyrazole,-   57)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(4-methoxyphenyl)carbamate,-   58)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(3-fluorophenyl)carbamate,-   59)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(4-chlorophenyl)carbamate,

60)1-benzyl-4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]-1H-pyrazole,

-   61)    2-fluoro-5-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]pyridine,-   62)    5-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]pyrimidine,-   63)    N-[4′-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)biphenyl-2-yl]acetamide,-   64)    4′-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)biphenyl-2-carboxamide,-   65)    N-[4′-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)biphenyl-3-yl]acetamide,-   66)    3-fluoro-4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]pyridine,-   67)    2-methoxy-5-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]pyridine,-   68)    4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]-3,5-dimethylisoxazole,-   69)    2-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(2-furylmethyl)carbamate,-   70)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1H-yl)ethyl(4-methylphenyl)carbamate,-   71)    4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzenesulfonamide,-   72)    4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzonitrile,-   73)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(cyclopentyl)carbamate,-   74)    4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)aniline,-   75)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    2-thienylcarbamate,-   76)    5-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]-1H-tetrazole,-   77)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(4-cyanophenyl)carbamate,-   78)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl[2-(2-thienyl)ethyl]carbamate,-   79)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(3,5-dimethylisoxazol-4-yl)carbamate,-   80)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    3-thienylcarbamate,-   81) 5-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-2-methoxyphenol,-   82)    5-[3-(benzyloxy)-4-methoxyphenyl]-1-(4-fluorophenyl)-1H-pyrazole,-   83)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(3,4-dichlorophenyl)carbamate,-   84)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(3,4-difluorophenyl)carbamate,-   85) 5-(3,4-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazole,-   86) 5-(3-ethoxy-4-methoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazole,-   87)    5-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-1-(4-fluorophenyl)-1H-pyrazole,-   88)    5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-(4-fluorophenyl)-1H-pyrazole,-   89)    5-[3,4-bis(difluoromethoxy)phenyl]-1-[4-(difluoromethoxy)phenyl]-1H-pyrazole,    and physiologically acceptable salts thereof,

wherein a compound listed above (in either a free base form or in theform of a pharmaceutically acceptable salt thereof) can also be in theform of a solvate (such as a hydrate),

wherein a compound listed above (in a free base form or solvate thereof,or in the form of a pharmaceutically acceptable salt or solvate thereof)can also be in the form of a polymorph, and

wherein if the compound exhibits chirality it can be in the form of amixture of enantiomers such as a racemate or a mixture of diastereomers,or can be in the form of a single enantiomer or a single diastereomer.

According to a further preferred compound and/or method aspect of theinvention, the compounds of Formulas I, II, III, IV, V, VI, VII and VIIIare selected from:

-   1)    1-cyclopentyl-3-ethyl-6-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-1H-indazole,-   2)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzoic    acid,-   3)    1-cyclopentyl-3-ethyl-6-(1-pyridin-2-yl-1H-pyrazol-5-yl)-1H-indazole,-   4)    1-cyclopentyl-6-[1-(3,4-difluorophenyl)-1H-pyrazol-5-yl]-3-ethyl-1H-indazole,-   5) 6-(1-benzyl-1H-pyrazol-5-yl)-1-cyclopentyl-3-ethyl-1H-indazole,-   6)    1-cyclopentyl-3-ethyl-6-(1-pyridin-4-yl-1H-pyrazol-5-yl)-1H-indazole,-   7)    1-cyclopentyl-3-ethyl-6-(1-piperidin-4-yl-1H-pyrazol-5-yl)-1H-indazole,-   8)    1-cyclopentyl-3-ethyl-6-[1-(4-pyrimidin-5-ylphenyl)-1H-pyrazol-5-yl]-1H-indazole,-   9)    1-cyclopentyl-3-ethyl-6-{1-[4-(1H-pyrazol-4-yl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   10)    1-cyclopentyl-3-ethyl-6-{1-[4-(1H-pyrrol-2-yl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   11)    1-cyclopentyl-3-ethyl-6-[1-(4-pyridin-3-ylphenyl)-1H-pyrazol-5-yl]-1H-indazole,-   12)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzamide,-   13)    1-cyclopentyl-3-ethyl-6-{1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   14)    1-cyclopentyl-3-ethyl-6-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-1H-indazole,-   15)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzonitrile,-   16)    6-[1-(4-chlorophenyl)-1H-pyrazol-5-yl]-1-cyclopentyl-3-ethyl-1H-indazole,-   17)    1-cyclopentyl-3-ethyl-6-[1-(4-methylphenyl)-1H-pyrazol-5-yl]-1H-indazole,-   18)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzenesulfonamide,-   19)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N-(methylsulfonyl)benzamide,-   20)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N-(ethylsulfonyl)benzamide,-   22)    1-cyclopentyl-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   24)    1-{4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenyl}ethanone,-   25)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N,N-diethylbenzamide,-   26)    1-cyclopentyl-6-{1-[4-(difluoromethoxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1H-indazole,-   27)    4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]morpholine,-   28) 4-{[5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]methyl}benzoic    acid,-   30)    5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole,-   31)    2-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)-1,3-thiazole,-   32) 1-benzyl-5-(3,4-dimethoxyphenyl)-1H-pyrazole,-   33)    2-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzoic    acid,-   34)    3-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzoic    acid,-   35)    1-[4-(3-furyl)phenyl]-5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazole,-   36)    4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-yl)methyl]-N-(phenylsulfonyl)benzamide,-   37)    N-[(4-methoxyphenyl)sulfonyl]-4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]benzamide,-   38)    N-[(4-fluorophenyl)sulfonyl]-4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]benzamide,-   39) tert-butyl    4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]piperazine-1-carboxylate,-   40) 4-[5-(3,4-dimethoxyphenyl)-1H-pyrazol-1-yl]pyridine,-   41)    4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)pyridine,-   42)    4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)piperidine,-   43)    1-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]piperazine,-   44)    1-(4-fluorobenzyl)-5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-4-methyl-1H-pyrazole,-   45) 5-(3-Bromo-4-methoxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazole,-   46)    5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1-[4-(1H-pyrazol-1-yl)phenyl]-1H-pyrazole,-   47)    3-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]pyridine,-   48)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(4-fluorophenyl)carbamate,-   49)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    benzylcarbamate,-   50)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    1-methylpropylcarbamate,-   51)    1-Isobutyl-5-(4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl)-1H-pyrazole,-   52)    5-[3,4-bis(difluoromethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazole,-   53)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    phenylcarbamate,-   54)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    propylcarbamate,-   55)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(2-fluorophenyl)carbamate,-   56)    5-[4-(difluoromethoxy)-3-methoxyphenyl]-1-(4-methoxyphenyl)-1H-pyrazole,-   57)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(4-methoxyphenyl)carbamate,-   58)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(3-fluorophenyl)carbamate,-   59)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(4-chlorophenyl)carbamate,-   60)    1-benzyl-4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]-1H-pyrazole,-   62)    5-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]pyrimidine,-   63)    N-[4′-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)biphenyl-2-yl]acetamide,-   64)    4′-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)biphenyl-2-carboxamide,-   65)    N-[4′-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)biphenyl-3-yl]acetamide,-   66)    3-fluoro-4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]pyridine,-   67)    2-methoxy-5-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]pyridine,-   68)    4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]-3,5-dimethylisoxazole,-   69)    2-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1yl)ethyl(2-furylmethyl)carbamate,-   70)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(4-methylphenyl)carbamate,-   71)    4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzenesulfonamide,-   72)    4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzonitrile,-   73)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(cyclopentyl)carbamate,-   74)    4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)aniline,-   75)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    2-thienylcarbamate,-   76)    5-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]-1H-tetrazole,-   77)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(4-cyanophenyl)carbamate,-   78)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl[2-(2-thienyl)ethyl]carbamate,-   79)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(3,5-dimethylisoxazol-4-yl)carbamate,-   80)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    3-thienylcarbamate,-   81) 5-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-2-methoxyphenol,-   83)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(3,4-dichlorophenyl)carbamate,-   84)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(3,4-difluorophenyl)carbamate,-   85) 5-(3,4-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazole,-   86) 5-(3-ethoxy-4-methoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazole,-   87)    5-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-1-(4-fluorophenyl)-1H-pyrazole,-   88)    5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-(4-fluorophenyl)-1H-pyrazole,-   89)    5-[3,4-bis(difluoromethoxy)phenyl]-1-[4-(difluoromethoxy)phenyl]-1H-pyrazole,

and physiologically acceptable salts thereof,

wherein a compound listed above (in either a free base form or in theform of a pharmaceutically acceptable salt thereof) can also be in theform of a solvate (such as a hydrate),

wherein a compound listed above (in a free base form or solvate thereof,or in the form of a pharmaceutically acceptable salt or solvate thereof)can also be in the form of a polymorph, and

wherein if the compound exhibits chirality it can be in the form of amixture of enantiomers such as a racemate or a mixture of diastereomers,or can be in the form of a single enantiomer or a single diastereomer.

According to a further preferred compound and/or method aspect of theinvention, the compounds of Formulas I, II, III, IV, V, VI, VII, VIII,and IX are selected from:

-   90) 4-[5-(3-ethyl-2-methyl-2H-indazol-6-yl)-1H-pyrazol-1-yl]benzoic    acid,-   91)    1,3-diethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   92)    1-(cyclopropylmethyl)-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   93)    3-ethyl-1-isopropyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-indazole,-   94)    3-ethyl-1-(2-methoxyethyl)-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   95)    6-[1-(1-acetylpiperidin-4-yl)-1H-pyrazol-5-yl]-1-cyclopentyl-3-ethyl-1H-indazole,-   96)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N,N-dimethylbenzenesulfonamide,-   97)    1-(ethoxymethyl)-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   98)    3-ethyl-1-(1-ethylpropyl)-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   99)    3-ethyl-2-(1-ethylpropyl)-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-2H-indazole,-   100)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-indazole,-   101)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-2-(tetrahydro-2H-pyran-2-ylmethyl)-2H-indazole,-   102)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-2-(2-pyrrolidin-1-ylethyl)-2H-indazole,-   103) Isopropyl    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxylate,-   104)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(2-pyrrolidin-1-ylethyl)-1H-indazole,-   105)    N-(sec-butyl)-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxamide,-   106)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyridin-3-yl-1H-indazole,-   107)    N-cyclopentyl-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxamide,-   108)    N,3-diethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxamide,-   109)    3-ethyl-N-(2-furylmethyl)-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxamide,-   110)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyrimidin-2-yl-1H-indazole,-   111)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyrimidin-5-yl-1H-indazole,-   112)    1-cyclopropyl-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   113)    2-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]quinoxaline,-   114)    1-{4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenyl}-N-methylmethanesulfonamide,-   115)    1-(3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazol-1-yl)-2-methylpropan-2-ol,-   116)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole,-   117)    1-(difluoromethyl)-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   118)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyridin-2-yl-1H-indazole,-   119)    1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   120)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydrofuran-3-yl)-1H-indazole,-   121) Tert-butyl    3-(3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazol-1-yl)pyrrolidine-1-carboxylate,-   122)    1-cyclopropyl-3-ethyl-6-(1-isopropyl-1H-pyrazol-5-yl)-1H-indazole,-   123) 1-cyclopropyl-3-ethyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-indazole,-   124) 1-cyclopropyl-3-ethyl-6-(1H-pyrazol-5-yl)-1H-indazole,-   125) 1-cyclopropyl-3-ethyl-6-(1-ethyl-1H-pyrazol-5-yl)-1H-indazole,-   126)    1-cyclopropyl-3-ethyl-6-(1-pyridin-4-yl-1H-pyrazol-5-yl)-1H-indazole,-   127)    2-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]quinoxaline,-   128)    {4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenyl}methanol,-   129)    2-{4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenyl}propan-2-ol,-   130)    1-{4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenyl}-N-methylmethanesulfonamide,-   131)    1-cyclopropyl-3-ethyl-6-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]-1H-indazole,-   132)    1-cyclopropyl-3-ethyl-6-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl]-1H-indazole,-   133)    1-cyclopropyl-6-[1-(1,1-dioxidotetrahydro-3-thienyl)-1H-pyrazol-5-yl]-3-ethyl-1H-indazole,-   134)    6-(1-cyclopentyl-1H-pyrazol-5-yl)-1-cyclopropyl-3-ethyl-1H-indazole,-   135)    1-cyclopentyl-3-ethyl-6-(1-{4-[(2-methoxyethoxy)methyl]phenyl}-1H-pyrazol-5-yl)-1H-indazole,-   136)    1-cyclopropyl-3-ethyl-6-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazol-5-yl]-1H-indazole,-   137)    6-{1-[3-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-1-cyclopropyl-3-ethyl-1H-indazole,-   138)    3-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenol,-   139)    3-ethyl-1-isopropyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-pyrazolo[3,4-b]pyridine,-   140)    2-{3-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenoxy}ethanol,-   141)    6-{1-[4-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-1-cyclopropyl-3-ethyl-indazole,-   142)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,-   143)    4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenol,-   144)    (4-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenyl)methanol,-   145)    2-(4-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenyl)propan-2-ol,-   146)    1-cyclopropyl-3-ethyl-6-{1-[3-(2-methoxyethoxy)phenyl]-1H-pyrazol-5yl}-1H-indazole,-   147)    1-cyclopropyl-3-ethyl-6-[1-(3-methoxyphenyl)-1H-pyrazol-5-yl]-1H-indazole,-   148)    1-cyclopropyl-3-ethyl-6-{1-[4-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-1H-indazole,-   149)    1-cyclopropyl-3-ethyl-6-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-1H-indazole,-   150)    1-cyclopropyl-3-ethyl-6-(1-pyrimidin-2-yl-1H-pyrazol-5-yl)-1H-indazole,-   151)    3-ethyl-1-(2-methoxypyridin-4-yl)-6-(1-pyrimidin-2-yl-1H-pyrazol-5-yl)-1H-indazole,-   152)    1-[4-(difluoromethoxy)phenyl]-5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazole-   153)    1-cyclopentyl-3-ethyl-6-[1-(pyridin-4-ylmethyl)-1H-pyrazol-5-yl]-1H-indazole-   154)    4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]pyridine-   155) 4-[5-(3-ethyl-1-methyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzoic    acid-   156)    4-[5-(3-ethyl-1-methyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzenesulfonamide-   157)    3-ethyl-1-methyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-   158)    4-[5-(3-ethyl-1-methyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzonitrile-   159)    4-[5-(3-ethyl-2-methyl-2H-indazol-6-yl)-1H-pyrazol-1-yl]benzenesulfonamide-   160)    3-ethyl-2-methyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-2H-indazole-   161)    4-[5-(3-ethyl-2-methyl-2H-indazol-6-yl)-1H-pyrazol-1-yl]benzonitrile-   162)    6-{1-[4-(difluoromethoxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-   163)    3-ethyl-6-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-   164)    3-ethyl-6-(1-pyridin-4-yl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-   165)    3-ethyl-6-(1-phenyl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-   166)    3-ethyl-6-(1-pyrimidin-2-yl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-   167)    3-ethyl-6-[1-(3-fluorophenyl)-1H-pyrazol-5-yl]-1-(tetrahydro-2H-pyran-4yl)-1H-pyrazolo[3,4-b]pyridine-   168)    3-ethyl-6-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-   169)    3-ethyl-6-[1-(3-methoxyphenyl)-1H-pyrazol-5-yl]-1-(tetrahydro-2H-pyran-4yl)-1H-pyrazolo[3,4-b]pyridine-   170)    6-{1-[4-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-   171)    6-{1-[3-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-   172)    4-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenol-   173)    3-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenol-   174)    6-{1-[3-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-   175)    6-{1-[4-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-   176)    2-(3-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenoxy)ethanol-   177)    2-(4-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenoxy)ethanol-   3-ethyl-6-{1-[3-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-   3-ethyl-6-{1-[4-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-   2-(3-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-yl]-1H-pyrazol-1-yl}phenoxy)ethanol-   2-(4-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-yl]-1H-pyrazol-1-yl}phenoxy)ethanol

and physiologically acceptable salts thereof,

wherein a compound listed above (in either a free base form or in theform of a pharmaceutically acceptable salt thereof) can also be in theform of a solvate (such as a hydrate),

wherein a compound listed above (in a free base form or solvate thereof,or in the form of a pharmaceutically acceptable salt or solvate thereof) can also be in the form of a polymorph, and

wherein if the compound exhibits chirality it can be in the form of amixture of enantiomers such as a racemate or a mixture of diastereomers,or can be in the form of a single enantiomer or a single diastereomer.

The following table presents the structures for selected compounds ofFormulas I-IX in accordance with the present invention:

1)

2)

3)

4)

5)

6)

7)

8)

9)

10)

11)

12)

13)

14)

15)

16)

17)

18)

19)

20)

21)

22)

23)

24)

25)

26)

27)

28)

29)

30)

31)

32)

33)

34)

35)

36)

37)

38)

39)

40)

41)

42)

43)

44)

45)

46)

47)

48)

49)

50)

51)

52)

53)

54)

55)

56)

57)

58)

59)

60)

61)

62)

63)

64)

65)

66)

67)

68)

69)

70)

71)

72)

73)

74)

75)

76)

77)

78)

79)

80)

81)

82)

83)

84)

85)

86)

87)

88)

89)

90)

91)

92)

93)

94)

95)

96)

97)

98)

99)

100)

101)

102)

103)

104)

105)

106)

107)

108)

109)

110)

111)

112)

113)

114)

115)

116)

117)

118)

119)

120)

121)

122)

123)

124)

125)

126)

127)

128)

129)

130)

131)

132)

133)

134)

135)

136)

137)

138)

139)

140)

141)

142)

143)

144)

145)

146)

147)

148)

149)

150)

151)

152)

153)

154)

155)

156)

157)

158)

159)

160)

161)

162)

163)

164)

165)

166)

167)

168)

169)

170)

171)

172)

173)

174)

175)

176)

177)

Preferred aspects include pharmaceutical compositions comprising acompound of this invention and a pharmaceutically acceptable carrierand, optionally, another active agent as discussed below. A furtherpreferred aspect includes a method of inhibiting a PDE4 enzyme,especially an isoenzyme, e.g., as determined by a conventional assay orone described herein, either in vitro or in vivo (in an animal, e.g., inan animal model, or in a mammal or in a human); a method of treating apsychiatric or neurological syndrome, e.g., depression and loss ofmemory, especially major depression and long-term memory, cognitiveimpairment or decline, memory impairment, etc.; a method of treating adisease state modulated by PDE4 activity, in a mammal, e.g., a human,e.g., those disease states mentioned herein.

Methods of the invention include, but are not limited to, methods ofenhancing cognition in a patient in whom such enhancement is desired,methods of treating a patient suffering from cognition impairment ordecline, methods of treating a patient having a disease involvingdecreased cAMP levels, methods of inhibiting PDE4 enzyme activity in apatient, methods of treating a patient suffering from memory impairmentdue to neurodegenerative disease, methods of treating a patientsuffering from depression, methods of treating a patient suffering froman allergic or inflammatory disease. All methods comprise administeringto the patient an effective amount of a compound of the invention.Preferably, the patient is human.

The compounds of the present invention may be prepared conventionally.Some of the known processes that can be used are described below. Allstarting materials are known or can be conventionally prepared fromknown starting materials.

Preparation of starting materials:

The starting materials for Formulas I and IV are prepared as shown inScheme 1. Thus, appropriately substituted benzaldehydes 3 (X=CH, N) aresubjected to Homer-Wadsworth-Emmons conditions with phosphonate 2. Theresulting olefin is not isolated, but heated to induce cyclization[Almirante, N.; Cerri, A.; Fedrizzi, G.; Marazzi, G.; Santagostino, M.Tetrahedron Lett., 1998, 39, 3287-3290] to provide the correspondingpyrazoles 5.

Alternatively, 3-substituted pyrazoles can be made frombeta-ketoaldehydes and hydrazine [Murray, W.; Wachter, M.; Barton, D.;Forenro-Kelly, Y. Synthesis, 1991, 18] or from various palladiumcouplings using a pyrazole aptly substituted in the 3 position, forexample with a bromine or a boron. [Cacchi, S.; Fabrizi, G.; Carnaio, A.Syn. Lett. 1997, 959-961];

Substitution on the pyrazole nitrogen is accomplished by treatment ofthe pyrazole 5 with an appropriate base such as NaH, LDA or K₂CO₃ in apolar aprotic solvent. This is followed by the addition of electrophileR³-L-X′, where X′ is a suitable leaving group such as a halogen orsulfonate (Cl, Br, methanesulfonyl, etc.). A mixture of substitutedpyrazoles 6a and 6b are obtained with the major isomer being the1.3-disubstituted pyrazoles (6a). These isomers can be separated byHPLC.

Reaction of pyrazole 5 with alkyl bromoacetate (preferably t-butylbromoacetate) gives pyrazole substituted acetate esters. These estersare saponified to acetic acid derivatives 6a and 6b (L=CH₂CO, R³=H) bytreatment with either an acid, such as trifluoroacetic acid, or use of abase, such as sodium hydroxide. Treatment of the resultant acetic acidproducts with thionyl chloride or oxalyl chloride generates thecorresponding acid chloride. Subsequent reaction with a nucleophile suchas an amine (e.g., aniline) gives the acetamide derivatives 6a and 6b(e.g., L=CH₂CONH, R³=phenyl). Similarly, the acetic acid derivative(L=CH₂CO₂, R₃=H) can be treated with HBTU or a suitable coupling reagent(i.e., DCC, HOBT, etc) and an amine compound to give the desiredacetamide analogues 6a and 6b.

Alternatively, (Scheme 3) compounds of the type 6a where R²=arylalkyl,alkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocyclic orheterocyclic-alkyl groups can be prepared by either Mitsunobu reactionbetween phenol 7b and an appropriate alcohol (R²OH) or alkylation with asuitable electrophile, R²—X′ (X′ is a suitable leaving group such as ahalogen or sulfonate (Cl, Br, methanesulfonyl etc.)), and an appropriatebase (i.e., K₂CO₃, NaH, NaOH). (R²=arylalkyl, alkyl, cycloalkyl,heteroalkyl, cycloalkylalkyl, heterocyclic and heterocyclic-alkylgroups.)

3-Aryloxy and 3-heteroaryloxy pyrazole derivatives of the type 6a (i.e.,where R² is aryl or heteroaryl) are prepared by cross coupling reactionof phenol 7b with aryl boronic acids using a copper catalyst in thepresence of an amine base. Suitable copper catalysts include copperdiacetate, copper(II) chloride, etc. Generally, halogenated solvents areutilized, such as chloroform, dichloromethane, 1,2-dichloroethane, andthe like. Commonly used bases include triethylamine,diisopropylethylamine, and pyrrolidine. Alternatively, 3-aryloxy and3-heteroaryloxy pyrazole compounds can be synthesized in an analogousmethod as described previously for 3-phenyloxyrolipram, which utilizesan Ullman type coupling reaction starting with iodobenzene and3-hydroxyrolipram [Schmiechen, R. et al., U.S. Pat. No. 4,193,926]. Theother regioisomer 6b may be formed in an analogous manner.

Compounds of Formulas II and V are synthesized in a similar mannerstarting from aldehyde 8. For these reactions, the ketone should beprotected before pyrazole formation and can be deprotected afterwards.Suitable protecting groups include, but are not limited to, ketals andcyclic ketals.

Compounds of Formulas III and VI are synthesized in a similar mannerstarting from aldehyde 9. [Marfat, A., et al., U.S. Pat. No. 6,262,040.]

Synthesis of 1,5-pyrazoles

A. Cross-Coupling Reactions

Alternatively, the 1,5-disubstiuted compounds of Formula IV through VIIcan be prepared from 1-hydroxypyrazole 10 (Scheme 4) (Eskildsen, J.,Vedso, P., Begtrup, M., Synthesis, 2001, 1053-1056. Eskildsen, J.,Kristensen, J., Vedso, P., Begtrup, M., J. Org. Chem., 2001, 66,8654-8656. Paulson, A. S., Eskildsen J., Vedso, P., Begtrup, M., J. Org.Chem., 2002, 67, 3904-3907). Thus, warming a solution of1-hydroxypyrazole 10 with an electrophile such as a benzyl bromide orα-bromoacetate in CHCl₃ to 60 to 100° C. provides2-substituted-pyrazol-1-oxides 11. Subsequent treatment with POCl₃ orPOBr₃ in a halogenated solvent such as CHCl₃ yields 5-halo-1-substitutedpyrazoles 12. Such 5-halo-1-substituted pyrazoles can undergocross-coupling type reaction with aryl boronic acids 2 (Z=B(OH)₂) or canbe metalated (e.g., halogen-magnesium exchange, transmetalation withZnCl₂) for a Negishi-type reaction with an aryl halide 2 (Z=halogen).

Alternatively, 1,5-disubstituted pyrazoles 6b can be prepared from2-aryldithianes 13 in a three step synthesis. Thus, dithianeintermediate 13 can be prepared by reaction of aldehyde 3 with propanedithiol and a Lewis acid catalyst such as BF₃-Et₂O in an aprotic solvent(Hatch, R. P., Shringarpure, J., Weinreb, S. M., J. Org. Chem., 1978,43, 4172-4177). Subsequent reaction of the alkyl lithium produceddithiane anion with appropriately substituted epoxides provides2,2-disubstituted dithianes 14. Oxidation of alcohol 14 to the protectedβ-keto dithiane followed by treatment with an appropriately substitutedhydrazine salt provides 1,5-disubstitued pyrazoles 6b.

Another method to prepare 1,5-disubstituted pyrazoles of type 6b isthrough condensation reaction between 1,3-diketo derivative 16 and asubstituted hydrazine (Nakamura, Toshio, et al., J. Med Chem, 2003, 46,5416; Penning, T. D., et al, J. Med. Chem., 1997, 40, 1347-1365. ) Theselectivity of this reaction for 1,5 versus 1,3-disubstituted pyrazolesvaries pending the substitution at R⁸. Formation of the1,5-disubstituted pyrazoles are favored when R⁸ is an electronwithdrawing group such as carboxylate or trifluoromethyl, or a smallgroup such as hydrogen. Starting 1,3-diketo derivatives 16 are preparedfrom acetophenone derivatives 15 by reaction with sodium hydride and anappropriately substituted ethyl acetate.

In a similar fashion, enamines of the type 17 undergo reaction withappropriately substituted hydrazines to provide target pyrazoles 6b(Yang, Ji, et al., J. Med. Chem. 2004, 47(6), 1547).

Compounds of Formula VIII can also be prepared using the generalprocedure described above.

Subsequent reaction with the appropriately substituted isocyanates inhalogenated solvents provides the desired carbamates. Compounds offormulas I-VIII where L is CH₂CH₂OCONHR³ can be prepared by the reactionof hydroxyethyl hydrazine with an enamine of the type 17 to form theethanol derivative 6b (L=CH₂CH₂OH).

Azaindazole analogs of formulae VI where X=N are prepared in a similarfashion as described above in Scheme 7 starting with 6-ketoazaindazoleanalog 21. This starting material is prepared from 2,6-dihalogenatedpyridines of the type 18 by selective lithiation at the 3-position by asterically hindered non-nucleophilic base such as LDA followed bytreatment with an appropriate substituted aldehyde such aspropionaldehyde to generate the corresponding secondary alcohol.(Radinov, R.; Chanev, C.; Haimova, M., Lithiation ofpolychloropyrimidines and dichloropyridines. J. Org. Chem. 1991, 5,4793-4796. ). Oxidation to the corresponding ketone can be performed bya number of methods such as with PCC in chloroform to generate3-ketosubstituted pyridine 19. Reaction of pyridine 19 with asubstituted hydrazine provides 6-halo-azaindazole 20. Treatment withNaCN produces the 6-cyano derivative which can then be converted totarget 21 by reaction with phosphoranes. (Reference: Taber, D. F.; Cai,L., Preparation of ketones from nitrites and phosphoranes. J. Org. Chem.2005, 70, 4887-4888. )

Alternatively, target compounds of formula VI or IX can be prepared from6-keto-indazole intermediates of the type 21 or 24 as described inScheme 7. Thus, Weinreb amide analog 22 is prepared by conventionalmethods from the previously described carboxylic acid. Treatment of 22with a strong base such as potassium tert-butoxide followed by additionof a suitable R⁶-bromide provides primarily 1-substituted indazoles 23with minor amounts of the 2-substituted analogs 24. Treatment of theWeinreb amide analog 23 with a Grignard reagent provides keyintermediate 21.

In addition, a variety of ethers can be synthesized by alkylation ofphenolic analogs 26 by reaction with various alkyl bromides to providetargets 27. In addition these phenols can be functionalized by Mitsunobureaction with an appropriate alcohol to provide compounds whereR⁹=OAlkyl. Still further, reaction with trifluoromethylsulfonyl chlorideprovides the triflate (R⁹=CF₃SO₃—) which can readily undergo Suzuki typereactions with boronic acids or Buchwald reactions with amines togenerate biaryls (R⁹=aryl or heteroaryl) and amino substituted compounds(R⁹=N(R)₂) respectively.

One of ordinary skill in the art will recognize that some of thecompounds of Formulas I, II, III, IV, V, VI, VII, VIII, IX and X canexist in different geometrical isomeric forms. In addition, some of thecompounds of the present invention possess one or more asymmetric atomsand are thus capable of existing in the form of optical isomers, as wellas in the form of racemic or nonracemic mixtures thereof, and in theform of diastereomers and diastereomeric mixtures inter alia. All ofthese compounds, including cis isomers, trans isomers, diastereomicmixtures, racemates, nonracemic mixtures of enantiomers, substantiallypure, and pure enantiomers, are within the scope of the presentinvention. Substantially pure enantiomers contain no more than 5% w/w ofthe corresponding opposite enantiomer, preferably no more than 2%, mostpreferably no more than 1%.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereomeric salts using an optically active acid or baseor formation of covalent diastereomers.

Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixturesof diastereomers can be separated into their individual diastereomers onthe basis of their physical and/or chemical differences by methods knownto those skilled in the art, for example, by chromatography orfractional crystallization. The optically active bases or acids are thenliberated from the separated diastereomeric salts.

A different process for separation of optical isomers involves the useof chiral chromatography (e.g., chiral HPLC columns), with or withoutconventional derivation, optimally chosen to maximize the separation ofthe enantiomers. Suitable chiral HPLC columns are manufactured byDiacel, e.g., Chiracel OD and Chiracel OJ among many others, allroutinely selectable. Enzymatic separations, with or withoutderivitization, are also useful. The optically active compounds ofFormulas I-X can likewise be obtained by utilizing optically activestarting materials in chiral syntheses processes under reactionconditions which do not cause racemization.

In addition, one of ordinary skill in the art will recognize that thecompounds can be used in different enriched isotopic forms, e.g.,enriched in the content of ²H, ³H, ¹¹C, ¹³C and/or ¹⁴C. In oneparticular embodiment, the compounds are deuterated. Such deuteratedforms can be made by the procedure described in U.S. Pat. Nos. 5,846,514and 6,334,997. As described in U.S. Pat. Nos. 5,846,514 and 6,334,997,deuteration can improve the efficacy and increase the duration of actionof drugs.

Deuterium substituted compounds can be synthesized using various methodssuch as described in: Dean, Dennis C.; Editor. Recent Advances in theSynthesis and Applications of Radiolabeled Compounds for Drug Discoveryand Development. [In: Curr., Pharm. Des., 2000; 6(10)] (2000), 110 pp.CAN 133:68895 AN 2000:473538 CAPLUS; Kabalka, George W.; Varma, RajenderS. The Synthesis of Radiolabeled Compounds via OrganometallicIntermediates. Tetrahedron (1989), 45(21), 6601-21, CODEN: TETRABISSN:0040-4020. CAN 112:20527 AN 1990:20527 CAPLUS; and Evans, E.Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem.(1981), 64(1-2), 9-32. CODEN: JRACBN ISSN: 0022-4081, CAN 95:76229 AN1981:476229 CAPLUS.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as pharmaceutically acceptable salts or prodrugsof all the compounds of the present invention for which salts orprodrugs can be prepared. Pharmaceutically acceptable salts includethose obtained by reacting the main compound, functioning as a base,with an inorganic or organic acid to form a salt, for example, salts ofhydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid,camphorsulfonic acid, oxalic acid, maleic acid, succinic acid and citricacid. Pharmaceutically acceptable salts also include those in which themain compound functions as an acid and is reacted with an appropriatebase to form, e.g., sodium, potassium, calcium, magnesium, ammonium, andcholine salts. Those skilled in the art will further recognize that acidaddition salts of the claimed compounds may be prepared by reaction ofthe compounds with the appropriate inorganic or organic acid via any ofa number of known methods. Alternatively, alkali and alkaline earthmetal salts are prepared by reacting the compounds of the invention withthe appropriate base via a variety of known methods.

The following are further examples of acid salts that can be obtained byreaction with inorganic or organic acids: acetates, adipates, alginates,citrates, aspartates, benzoates, benzenesulfonates, bisulfates,butyrates, camphorates, digluconates, cyclopentanepropionates,dodecylsulfates, ethanesulfonates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, fumarates, hydrobromides,hydroiodides, 2-hydroxy-ethanesulfonates, lactates, maleates,methanesulfonates, nicotinates, 2-naphthalenesulfonates, oxalates,palmoates, pectinates, persulfates, 3-phenylpropionates, picrates,pivalates, propionates, succinates, tartrates, thiocyanates, tosylates,mesylates and undecanoates.

For example, the pharmaceutically acceptable salt can be ahydrochloride, a hydroformate, hydrobromide, or a maleate.

Preferably, the salts formed are pharmaceutically acceptable foradministration to mammals. However, pharmaceutically unacceptable saltsof the compounds are suitable as intermediates, for example, forisolating the compound as a salt and then converting the salt back tothe free base compound by treatment with an alkaline reagent. The freebase can then, if desired, be converted to a pharmaceutically acceptableacid addition salt.

One of ordinary skill in the art will also recognize that some of thecompounds of Formulas I-X can exist in different polymorphic forms. Asknown in the art, polymorphism is an ability of a compound tocrystallize as more than one distinct crystalline or “polymorphic”species. A polymorph is a solid crystalline phase of a compound with atleast two different arrangements or polymorphic forms of that compoundmolecule in the solid state. Polymorphic forms of any given compound aredefined by the same chemical formula or composition and are as distinctin chemical structure as crystalline structures of two differentchemical compounds.

One of ordinary skill in the art will further recognize that compoundsof Formulas I-X can exist in different solvate forms. Solvates of thecompounds of the invention may also form when solvent molecules areincorporated into the crystalline lattice structure of the compoundmolecule during the crystallization process. For example, suitablesolvates include hydrates, e.g., monohydrates, dihydrates,sesquihydrates, and hemihydrates.

The compounds of the invention can be administered alone or as an activeingredient of a formulation. Thus, the present invention also includespharmaceutical compositions of one or more compounds of Formulas I, II,III, IV, V, VI, VII, VIII, IX and X containing, for example, one or morepharmaceutically acceptable carriers.

Numerous standard references are available that describe procedures forpreparing various formulations suitable for administering the compoundsaccording to the invention. Examples of potential formulations andpreparations are contained, for example, in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington's Pharmaceutical Sciences (Arthur Osol, editor),1553-1593 (current edition).

In view of their high degree of selective PDE4 inhibition, the compoundsof the present invention can be administered to anyone requiring PDE4inhibition. Administration may be accomplished according to patientneeds, for example, orally, nasally, parenterally (subcutaneously,intravenously, intramuscularly, intrastemally and by infusion) byinhalation, rectally, vaginally, topically and by ocular administration.

Various solid oral dosage forms can be used for administering compoundsof the invention including such solid forms as tablets, gelcaps,capsules, caplets, granules, lozenges and bulk powders. The compounds ofthe present invention can be administered alone or combined with variouspharmaceutically acceptable carriers, diluents (such as sucrose,mannitol, lactose, starches) and excipients known in the art, includingbut not limited to suspending agents, solubilizers, buffering agents,binders, disintegrants, preservatives, colorants, flavorants, lubricantsand the like. Time release capsules, tablets and gels are alsoadvantageous in administering the compounds of the present invention.

Various liquid oral dosage forms can also be used for administeringcompounds of the inventions, including aqueous and non-aqueoussolutions, emulsions, suspensions, syrups, and elixirs. Such dosageforms can also contain suitable inert diluents known in the art such aswater and suitable excipients known in the art such as preservatives,wetting agents, sweeteners, flavorants, as well as agents foremulsifying and/or suspending the compounds of the invention. Thecompounds of the present invention may be injected, for example,intravenously, in the form of an isotonic sterile solution. Otherpreparations are also possible.

Suppositories for rectal administration of the compounds of the presentinvention can be prepared by mixing the compound with a suitableexcipient such as cocoa butter, salicylates and polyethylene glycols.Formulations for vaginal administration can be in the form of a pessary,tampon, cream, gel, paste, foam, or spray formula containing, inaddition to the active ingredient, such suitable carriers as are knownin the art.

For topical administration, the pharmaceutical composition can be in theform of creams, ointments, liniments, lotions, emulsions, suspensions,gels, solutions, pastes, powders, sprays, and drops suitable foradministration to the skin, eye, ear or nose. Topical administration mayalso involve transdermal administration via means such as transdermalpatches.

Aerosol formulations suitable for administering via inhalation also canbe made. For example, for treatment of disorders of the respiratorytract, the compounds according to the invention can be administered byinhalation in the form of a powder (e.g., micronized) or in the form ofatomized solutions or suspensions. The aerosol formulation can be placedinto a pressurized acceptable propellant.

The compounds can be administered as the sole active agent or incombination with other pharmaceutical agents such as other agents usedin the treatment of cognitive impairment and/or in the treatment ofpsychosis, e.g., other PDE4 inhibitors, calcium channel blockers,chloinergic drugs, adenosine receptor modulators, ampakines, NMDA-Rmodulators, mGluR modulators, and cholinesterase inhibitors (e.g.,donepezil, rivastigimine, and galanthamine). In such combinations, eachactive ingredient can be administered either in accordance with theirusual dosage range or a dose below their usual dosage range.

The present invention further includes methods of treatment that involveinhibition of PDE4 enzymes. Thus, the present invention includes methodsof selective inhibition of PDE4 enzymes in patients, such as animals,e.g., mammals, especially humans, wherein such inhibition has atherapeutic effect, such as where such inhibition may relieve conditionsinvolving neurological syndromes, such as the loss of memory, especiallylong-term memory. Such methods comprise administering to a patient inneed thereof, such as an animal, especially a mammal, most especially ahuman, an inhibitory amount of a compound, alone or as part of aformulation, as disclosed herein.

The condition of memory impairment is manifested by impairment of theability to learn new information and/or the inability to recallpreviously learned information. Memory impairment is a primary symptomof dementia and can also be a symptom associated with such diseases asAlzheimer's disease, schizophrenia, Parkinson's disease, Huntington'sdisease, Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovasculardisease, head trauma as well as age-related cognitive decline.

Dementias are diseases that include memory loss and additionalintellectual impairment separate from memory. The present inventionincludes methods for treating patients suffering from memory impairmentin all forms of dementia. Dementias are classified according to theircause and include: neurodegenerative dementias (Alzheimer's, Parkinson'sdisease, Pick's disease), vascular (Infarcts, Hemorrhage, CardiacDisorders), mixed vascular and Alzheimer's, bacterial meningitis,Creutzfeld-Jacob Disease, multiple sclerosis, traumatic (subduralhematoma or traumatic brain injury), infectious (HIV), toxic (heavymetals, alcohol, medications), metabolic (Vitamin B₁₂ or folatedeficiency), CNS hypoxia, Cushing's disease, psychiatric (depression andschizophrenia) and hydrocephalus.

The present invention also includes methods for treating memory lossseparate from dementias, including mild cognitive impairment (MCI) andage-related cognitive decline. The present invention includes methods oftreatment for memory impairment as a result of disease includingHuntington's disease and Down's syndrome. According to another aspect,the invention includes methods for treating memory loss fromanesthetics, chemotherapy, radiation treatment, post-surgical trauma,post-traumatic stress disorder (PTSD), obesity, and diabetes.

The compounds of the invention can also be used to treat schizophrenia,bipolar or manic depression, major depression, and drug addiction. PDE4inhibitors can be used to raise cAMP levels and prevent neurons fromundergoing apoptosis. PDE4 inhibitors are also known to beanti-inflammatory. The combination of preventing neuronal apoptosis andinhibiting inflammatory responses make these compounds useful to treatneurodegeneration resulting from any disease or injury, includingstroke, Alzheimer's disease, multiple sclerosis, amyolaterosclerosis(ALS), and multiple systems atrophy (MSA), as well as spinal injury.

PDE4 inhibitors have been shown to produce antidepressant effects inhumans and antidepressant-like effects in animal models of depression.Clinical studies in humans suffering from major depression havedemonstrated efficacy of the PDE4 inhibitor, rolipram, with comparableresults in some of these studies to those of desipramine [Bobon D,Breulet M, Gerard-Vandenhove M A, Guito-Goffioul F, Plomteux G,Satre-Hernandez M, Schratzer M, Troisfontaines B, von Frenckell R,Wachtel H (1988) Is Phosphodiesterase Inhibition a New Mechanism ofAntidepressant Action? Eur Arch Psychiatr Neurol Sci., 238: 2-6; Meya U,Wachtel H, Sastre-Hemandez M (1991) Inhibition of Phosphodiesterase asan Antidepressive Mechanism: Clinical Properties of Rolipram. In AnsseauM, von Frenckell, Franck G (eds) Biological Markers of Depression: Stateof the art, Elsevier Science Publishers B. V., Pp. 209-213; Zhu J, MixE, Winblad B (2001) The Antidepressant and Anti-inflammatory Effects ofRolipram in the Central Nervous System. CNS Drug Reviews, 7: 387-398].Rolipram was active in a number of biochemical and behavioralpreclinical models of antidepressant activity [Wachtel H (1983)Potential Antidepressant Activity of Rolipram and other Selective CyclicAdenosine 3′,5′-Monophosphate Phosphodiesterase Inhibitors.Neuropharmacology, 22: 267-272; and Wachtel H., Schneider H H (1986)Rolipram, a novel antidepressant drug, reverses the hypothermia andhypokinesia of monoamine-depleted mice by an action beyond postsynapticmonoamine receptors. Neuropharmacology, 25: 1119-1126]. More recently,studies with rolipram have demonstrated efficacy of this compound in thetail suspension and forced swimming models of antidepressant activity;these effects were eliminated in animals transgenically modified to lackthe PDE4D subtype suggesting that the antidepressant effects of rolipramare mediated by its inhibition of the PDE4 enzyme, specifically thePDE4D subtype [Zhang H-T, Huang Y, Jin S-L, Frith S A, Suvama N, ContiM, O'Donnell J M (2002) Antidepressant-like Profile and ReducedSensitivity to Rolipram in Mice Deficient in the PDE4D PhosphodiesteraseEnzyme, Neuropsychopharmacology, 27: 587-595].

Thus, in accordance with a preferred embodiment, the present inventionincludes methods of treating patients suffering from memory impairmentdue to, for example, mild cognitive impairment due to aging, Alzheimer'sdisease, schizophrenia, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeld-Jakob disease, depression, aging, headtrauma, stroke, CNS hypoxia, cerebral senility, multiinfarct dementiaand other neurological conditions, as well as HIV and cardiovasculardiseases, comprising administering an effective amount of a compoundaccording to Formulas I, II, III, IV, V, VI, VII, VIII, IX and X or apharmaceutically acceptable salt or solvate (e.g., hydrate) thereof, ora solvate of a pharmaceutically acceptable salt thereof.

A subject or patient in whom administration of the therapeutic compoundis an effective therapeutic regimen for a disease or disorder ispreferably a human, but can be any animal, including a laboratory animalin the context of a clinical trial or screening or activity experiment.Thus, as can be readily appreciated by one of ordinary skill in the art,the methods, compounds and compositions of the present invention areparticularly suited to administration to any animal, particularly amammal, and including, but by no means limited to, humans, domesticanimals, such as feline or canine subjects, farm animals, such as butnot limited to bovine, equine, caprine, ovine, and porcine subjects,wild animals (whether in the wild or in a zoological garden), researchanimals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats,etc., avian species, such as chickens, turkeys, songbirds, etc., i.e.,for veterinary medical use.

As mentioned, the compounds of the invention also exhibitanti-inflammatory activity. As a result, the inventive compounds areuseful in the treatment of a variety of allergic and inflammatorydiseases, particularly disease states characterized by decreased cyclicAMP levels and/or elevated phosphodiesterase 4 levels. Thus, inaccordance with a further embodiment of the invention, there is provideda method of treating allergic and inflammatory disease states,comprising administering an effective amount of a compound according toFormulas I, II, III, IV, V, VI, VII, VIII, IX and X or apharmaceutically acceptable salt or solvate (e.g., hydrate) thereof, ora solvate of a pharmaceutically acceptable salt thereof. Such diseasestates include: asthma, chronic bronchitis, chronic obstructivepulmonary disease (COPD), atopic dermatitis, urticaria, allergicrhinitis, allergic conjunctivitis, vernal conjunctivitis, esoniophilicgranuloma, psoriasis, inflammatory arthritis, rheumatoid arthritis,septic shock, ulcerative colitis, Crohn's disease, reperfusion injury ofthe myocardium and brain, chronic glomerulonephritis, endotoxic shock,adult respiratory distress syndrome, cystic fibrosis, emphysema,arterial restenosis, artherosclerosis, keratosis, rheumatoidspondylitis, osteoarthritis, pyresis, diabetes mellitus, pneumoconiosis,chronic obstructive airways disease, chronic obstructive pulmonarydisease, toxic and allergic contact eczema, atopic eczema, seborrheiceczema, lichen simplex, sunburn, pruritis in the anogenital area,alopecia areata, hypertrophic scars, discoid lupus erythematosus,follicular and wide-area pyodermias, endogenous and exogenous acne, acnerosacea, Beghet's disease, anaphylactoid purpura nephritis, inflammatorybowel disease, leukemia, multiple sclerosis, gastrointestinal diseases,autoimmune diseases, osteoporosis, and the like. The compounds can alsobe used in a method of treating patients suffering from disease statescharacterized by decreased NMDA function, such as schizophrenia. Thecompounds may also be used for neuronal regeneration. The compounds canalso be used to treat psychosis characterized by elevated levels ofPDE4, for example, various forms of depression, such as manicdepression, major depression, and depression associated with psychiatricand neurological disorders. The compounds may additionally be used forneurogenesis.

The use of trisubstituted phenyl derivatives for treating asthma,chronic bronchitis, psoriasis, allergic rhinitis, and other inflammatorydiseases, and for inhibiting tumor necrosis factor is known within theart. See, e.g., WO 98/58901, JP 11-189577, JP 10-072415, WO 93/25517, WO94/14742, U.S. Pat. No. 5,814,651, and U.S. Pat. No. 5,935,978. Thesereferences describe 1,3,4-trisubstituted phenyl compounds said toexhibit PDE4 inhibition activity. They also describe assays fordetermining PDE4 inhibition activity, and methods for synthesizing suchcompounds. The entire disclosures of these documents are herebyincorporated by reference.

PDE4 inhibitors may be used to prevent or ameliorate osteoporosis, as anantibiotic, for treatment of cardiovascular disease by mobilizingcholesterol from atherosclerotic lesions, to treat rheumatoid arthritis(RA), for long-term inhibition of mesenchymal-cell proliferation aftertransplantation, for treatment of urinary obstruction secondary tobenign prostatic hyperplasia, for suppression of chemotaxis andreduction of invasion of colon cancer cells, for treatment of B cellchronic lymphocytic leukemia (B-CLL), for inhibition of uterinecontractions, to attenuate pulmonary vascular ischemia-reperfusioninjury (IRI), for corneal hydration, for inhibition of IL-2R expressionand thereby abolishing HIV-1 DNA nuclear import into memory T cells, foraugmentation of glucose-induced insulin secretion, in both theprevention and treatment of colitis, and to inhibit mast celldegranulation.

The invention is also suitable for use in the treatment of a class ofdisorders known as polyglutamine-repeat diseases. These diseases share acommon pathogenic mutation. The expansion of a CAG repeat, which encodesthe amino acid glutamine, within the genome leads to production of amutant protein having an expanded polyglutamine region. For example,Huntington's disease has been linked to a mutation of the proteinhuntingtin. In individuals who do not have Huntington's disease,huntingtin has a polyglutamine region containing about 8 to 31 glutamineresidues. For individuals who have Huntington's disease, huntingtin hasa polyglutamine region with over 37 glutamine residues. Aside fromHuntington's disease (HD), other known polyglutamine-repeat diseases andthe associated proteins are: dentatorubral-pallidoluysian atrophy, DRPLA(atrophin-1); spinocerebellar ataxia type-1 (ataxin-1); spinocerebellarataxia type-2 (ataxin-2); spinocerebellar ataxia type-3 also calledMachado-Joseph disease, MJD (ataxin-3); spinocerebellar ataxia type-6(alpha 1a-voltage dependent calcium channel); spinocerebellar ataxiatype-7 (ataxin-7); and spinal and bulbar muscular atrophy, SBMA, alsoknown as Kennedy disease (androgen receptor).

Thus, in accordance with a further aspect of the invention, there isprovided a method of treating a polyglutamine-repeat disease or CAGrepeat expansion disease comprising administering to a patient,especially a human, a therapeutically effective amount of a compoundaccording to Formulas I-X or a pharmaceutically acceptable salt orsolvate (e.g., hydrate) thereof, or a solvate of a pharmaceuticallyacceptable salt thereof. In accordance with a further embodiment, thereis provided a method of treating Huntington's disease (HD),dentatorubral-pallidoluysian atrophy (DRPLA), spinocerebellar ataxiatype-1, spinocerebellar ataxia type-2, spinocerebellar ataxia type-3(Machado-Joseph disease), spinocerebellar ataxia type-6, spinocerebellarataxia type-7, or spinal and bulbar muscular atrophy, comprisingadministering to a patient, especially a human, a therapeuticallyeffective amount of a compound according to Formulas I-X or apharmaceutically acceptable salt or solvate (e.g., hydrate) thereof, ora solvate of a pharmaceutically acceptable salt thereof.

The compounds of the present invention can be administered as the soleactive agent or in combination with other pharmaceutical agents such asother agents used in the treatment of cognitive impairment and/or in thetreatment of psychosis, e.g., other PDE4 inhibitors, PDE10 inhibitors,calcium channel blockers, chloinergic drugs, adenosine receptormodulators, ampakines, NMDA-R modulators, mGluR modulators, andcholinesterase inhibitors (e.g., donepezil, rivastigimine, andgalanthamine). In such combinations, each active ingredient can beadministered either in accordance with their usual dosage range or adose below their usual dosage range.

The compounds of Formulas I-X can be administered as the sole activeagent or in combination with other pharmaceutical agents such as otheragents used in the treatment of allergic and/or inflammatory conditions,e.g. respiratory conditions. Suitable examples of other pharmaceuticalagents which may be used in combination with the compounds of thepresent invention include, but are not limited to, other PDE-4inhibitors, 5-lipoxygenase (5-LO) inhibitors or 5-lipoxygenaseactivating protein (FLAP) antagonists (e.g., zileuton, fenleuton),leukotriene antagonists (LTRAs) including antagonists of LTB₄, LTC₄,LTD₄, and LTE₄ (e.g., ontazolast, ablukast, pranlukast, verlukast,zariflukast, montelukast, zileuton), histaminic receptor antagonists,including H1 and H3 antagonists (e.g., cetirizine, loratidine,desloratidine, fexofenadine, astemizole, azelastine, chlorpheniramine,cimetidine, ranitidine, famotidine, nizatidine), α₁, and α₂ adrenoceptoragonist vasoconstrictor sympathomimetic agents for decongestant use(e.g., propylhexedrine, phenylephrine, phenylpropanolamine,pseudoephedrine, naphazoline hydrochloride), muscarinic receptor (M1,M2, and M3) antagonists (e.g., ipratropium salts, namely bromide,tiotropium salts, namely bromide, oxitropium salts, namely bromide,perenzepine, and telenzepine), anticholinergic agents, β₁ to β₄ (e.g.β₂) adrenoceptor agonists (e.g., isoprenaline, albuterol, salbutamol,formoterol, salmeterol), COX-1 inhibitors (NSAIDs), COX-2 selectiveinhibitors, nitric oxide NSAIDs, oral or inhaled glucocorticosteroids(e.g., prednisone, prednisolone, flunisolide, triamcinolone acetonide,beclomethasone diproprionate), acetylcholinesterase inhibitors (e.g.,aricept), and adenosine A2a receptor agonists. Further examples ofsuitable other pharmaceutical agents which may be used in combinationwith the compounds of the present invention are disclosed in U.S. Pat.Nos. 6,559,168 and 6,756,392, which are hereby incorporated by referencein their entireties. In such combinations, each active ingredient can beadministered either in accordance with their usual dosage range or adose below its usual dosage range.

The compounds of the invention are also suitable for use in thetreatment of asbestos-related diseases or disorders. See, for example,U.S. Published Application No. 2005/0142104, which is herebyincorporated by reference in its entirety.

Thus, in accordance with a further aspect of the invention, there isprovided a method of treating asbestos-related diseases or disorderscomprising administering to a patient, such as a mammal, e.g., a human,a therapeutically effective amount of a compound of the invention (e.g.,in the form of a pharmaceutically acceptable salt or solvate (e.g.,hydrate) thereof). In accordance with a further embodiment, there isprovided a method of treating, for example, mesothelioma, asbestosis,pleural effusion, pleural plaque, pleural calcification, diffuse pleuralthickening, round atelectasis, and bronchogenic carcinoma, comprisingadministering to a patient, such as a mammal, e.g., a human, atherapeutically effective amount of a compound of the invention (e.g.,in the form of a pharmaceutically acceptable salt or solvate (e.g.,hydrate) thereof).

The compounds of the present invention may also be administered incombination with other known therapeutics for the treatment ofasbestos-related diseases or disorders including, but not limited to,other PDE-4 inhibitors, anti-cancer agents, antibiotics,anti-inflammatory agents, cytokines, steroids, immunomodulatory agents,immunosuppressive agents, and combinations thereof. In addition, thecompounds of the present invention can be used in combination withconventional therapies used to treat, prevent, or manageasbestos-related diseases or disorders, including, but not limited to,chemotherapy, surgery, radiation therapy, photodynamic therapy, andcombinations thereof.

When used in combination with one or more additional pharmaceuticalagent or agents for the treatment of asbestos-related diseases ordisorders, the compounds of the present invention may be administeredprior to, concurrently with, or following administration of theadditional pharmaceutical agent or agents. When used in combination withone or more conventional therapies for the treatment of asbestos-relateddiseases or disorders, the compounds of the present invention may beadministered prior to, concurrently with, or following the conventionaltherapy.

The dosages of the compounds of the present invention depend upon avariety of factors including the particular syndrome to be treated, theseverity of the symptoms, the route of administration, the frequency ofthe dosage interval, the particular compound utilized, the efficacy,toxicology profile, pharmacokinetic profile of the compound, and thepresence of any deleterious side-effects, among other considerations.

The compounds of the invention are typically administered at dosagelevels and in a mammal customary for PDE4 inhibitors such as those knowncompounds mentioned above. For example, the compounds can beadministered, in single or multiple doses, by oral administration at adosage level of generally 0.001-100 mg/kg/day, for example, 0.01-100mg/kg/day, preferably 0.1-70 mg/kg/day, especially 0.5-10 mg/kg/day.Unit dosage forms can contain generally 0.01-1000 mg of active compound,for example, 0.1-50 mg of active compound. For intravenousadministration, the compounds can be administered, in single or multipledosages, at a dosage level of, for example, 0.001-50 mg/kg/day,preferably 0.001-10 mg/kg/day, especially 0.01-1 mg/kg/day. Unit dosageforms can contain, for example, 0.1-10 mg of active compound.

In carrying out the procedures of the present invention, it is of courseto be understood that reference to particular buffers, media, reagents,cells, culture conditions and the like are not intended to be limiting,but are to be read so as to include all related materials that one ofordinary skill in the art would recognize as being of interest or valuein the particular context in which that discussion is presented. Forexample, it is often possible to substitute one buffer system or culturemedium for another and still achieve similar, if not identical, results.Those of skill in the art will have sufficient knowledge of such systemsand methodologies so as to be able, without undue experimentation, tomake such substitutions as will optimally serve their purposes in usingthe methods and procedures disclosed herein.

The present invention will now be further described by way of thefollowing non-limiting examples. In applying the disclosure of theseexamples, it should be kept clearly in mind that other and differentembodiments of the methods disclosed according to the present inventionwill no doubt suggest themselves to those of skill in the relevant art.

In the foregoing and in the following examples, all temperatures are setforth uncorrected in degrees Celsius; and, unless otherwise indicated,all parts and percentages are by weight.

The entire disclosures of all applications, patents and publications,cited above and below, are hereby incorporated by reference in theirentirety.

EXAMPLES

All spectra were recorded at 300 MHz on a Bruker Instruments NMR unlessotherwise stated. Coupling constants (J) are in Hertz (Hz) and peaks arelisted relative to TMS (δ 0.00 ppm). Sulfonic acid ion exchange resins(SCX) were purchased from Varian Technologies. Analytical HPLC wasperformed on 4.6 mm×100 mm Waters Sunfire RP C18 5 μm column using (i) agradient of 20/80 to 80/20 acetonitrile (0.1% formic acid)/water (0.1%formic acid) over 6 min (Method A), (ii) a gradient of 20/80 to 80/20acetonitrile (0.1% formic acid)/water (0.1% formic acid) over 8 min(Method B), (iii) a gradient of 40/60 to 80/20 acetonitrile (0.1% formicacid)/water (0.1% formic acid) over 6 min (Method C), (iv) a gradient of40/60 to 80/20 acetonitrile (0.1% formic acid)/water (0.1% formic acid)over 8 min (Method D), (v) an isocratic eluent of 80/20acetonitrile/water (0.1% formic acid) over 8 minutes (Method E), (vi) ora gradient of 10/90 to 90/10 acetonitrile (0.1% formic acid)/water (0.1%formic acid) over 6 min (Method F). Preparative HPLC was performed on 30mm×100 mm Xtera Prep RP₁₈ 5μ columns using an 8 min gradient of 95/5 to20/80 water (0.1% formic acid)/acetonitrile (0.1% formic acid).

Example 1 Example 1A Synthesis of4-Methoxy-3-(3R)-tetrahydrofuryloxybenzaldehyde

3-Hydroxy-4-methoxybenzaldehyde (7.6 g; 50 mmol) was dissolved in THF(200 mL) followed by addition of (S)-3-hydroxytetrahydrofuran (6.0 mL;75 mmol) and triphenylphosphine (19.7 g; 75 mmol). The resultingsolution was cooled to 5° C. and diisopropyl azodicarboxylate (14.8 mL;75 mmol) was added dropwise over 10 minutes. The clear orange solutionwas stirred at ambient temperature for 16 hours. Thin layerchromatography analysis using a 1:1 mixture of hexane/ethyl acetatedetermined the reaction to be complete. The solvent was removed underreduced pressure and the residue was taken up in ethyl acetate (60 mL)and extracted twice with 20% aqueous sodium bisulfite (150mL/extraction). The extracts were pooled and washed with ethyl acetate(75 mL). The aqueous layer was basified with solid sodium hydroxide (26g) and then extracted with 3×150 mL of ethyl acetate (150mL/extraction). The organic extracts were pooled, washed with 40 mL ofbrine, dried (Na₂SO₄), and concentrated to afford 7.4 g (66%) of a paleyellow oil. ¹H NMR (CDCl₃; 300 MHz) δ 2.2-2.4 (m, 2H); 3.8-4.1 (m, 7H);5.0 (m, 1H); 7.0 (d, 1H); 7.4 (s, 1H); 7.5 (d, 1H); 9.9 (s, 1H). ES-MS[M+H]+=223.2

The following compounds were prepared in a similar fashion withdifferent starting materials:

-   1-Bromo-4-methoxy-3-(3R)-tetrahydrofuranyloxybenzene.-   4-Methoxy-3-(3S)-tetrahydrofuryloxybenzaldehyde.

Example 1B Synthesis of3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole

Sodium hydride (60% in mineral oil, 1.51 g, 37.7 mmol) was suspended inTHF (20 mL) and cooled to 5° C. followed by addition ofdiethoxyphosphorylacetaldehyde tosylhydrazone (6.51 g, 18.7 mmol) in THF(20 mL) over 10 minutes. After stirring for 30 minutes at 5° C., theyellow suspension was treated with a solution of4-methoxy-3-(3R)-tetrahydrofuryloxybenzaldehyde (2.84 g, 12.8 mmol) inTHF (20 mL) and stirred for 1 hour at room temperature and 16 hours at80° C. in an oil bath. After cooling to room temperature, the reactionwas poured into 5% aqueous NaH₂PO₄ and extracted with ethyl acetate. Theextract was washed with water and brine, dried over Na₂SO₄ andconcentrated to afford a yellow solid. Recrystallization from ethylacetate furnished 1.9 g (57%) of3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole in two cropsas light yellow solids. (mp 149-151° C.); ¹H NMR (CDCl₃, 300 MHz) δ 2.23(m, 2H), 3.85-4.10 (m, 4H), 3.89 (s, 3H), 5.02 (m, 1H), 6.54 (m, 1H),6.92 (m, 1H), 7.25 (m, 2H), 7.60 (m, 1H); MS [M+H]=261.

The following compounds were prepared in a similar fashion withdifferent starting materials:

-   3-(3,4-Dimethoxyphenyl)-1H-pyrazole-   3-(3-Cyclopentyloxy-4-methoxyphenyl)-1H-pyrazole-   3-[3,4-Bis(difluoromethoxy)phenyl]-1H-pyrazole-   3-[4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole-   3-(3-Benzyloxy-4-methoxyphenyl)pyrazole-   3-[3-(2,3-Difluorobenzyloxy)-4-methoxyphenyl]pyrazole

Example 2 Synthesis of1-(2,3-difluorobenzyl)-3-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole

3-[4-Methoxy-3-(3R)tetrahydrofuranyloxyphenyl]-1H-pyrazole (243 mg, 0.96mmol) was dissolved in DMF (8 mL) at room temperature and treated withsodium hydride (75 mg, 1.86 mmol) with stirring for 3 hours. Thereaction mixture was treated with a solution of 2,3-difluorobenzylbromide (0.35 mL, 2.79 mmol) in DMF (1 mL) and stirred at roomtemperature for 16 hours. The reaction was diluted with ethyl acetateand washed with water three times and brine once. The organic layer wasdried over sodium sulfate and concentrated to an oil which was purifiedon a column of silica gel using a hexane/ethyl acetate gradient. Tubescontaining the compound were pooled and evaporated under vacuum toafford 327 mg (90%) of1-(2,3-difluorobenzyl)-3-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazoleas a colorless oil. MS [M+H]=387; ¹H NMR (CDCl₃, 300 MHz) δ 2.23 (m,2H), 3.8-4.1 (m, 4H), 3.92 (s, 3H), 5.1 (m, 1H), 5.4 (s, 2H), 6.5 (s,1H), 6.9 (m, 2H), 6.95-7.11 (m, 2H), 7.3 (m, 2H), 7.45 (s, 1H). A minorproduct consisting of1-(2,3-difluorobenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxy-phenyl]-1H-pyrazolewas also formed, which can be separated and isolated by preparative HPLC(see, e.g., Example 3).

The following compounds were prepared in a similar fashion withdifferent starting materials (in some cases, the 5-regioisomer was alsoformed and could be separated by methods known in the art such aspreparative HPLC):

-   3-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2-methylbenzyl)-1H-pyrazole,-   3-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(2,3-difluorobenzyl)-1H-pyrazole,-   3-(3-Cyclopentyloxy-4-methoxyphenyl)-1-(4-nitrobenzyl)-1H-pyrazole,-   3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(2-methylbenzyl)-1H-pyrazole,-   1-(4-Aminobenzyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1H-pyrazole,-   3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(4-nitrobenzyl)-1H-pyrazole,-   1-(4-Aminobenzyl)-3-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole,-   3-[4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(4-nitrobenzyl)-1H-pyrazole,-   3-[4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(2-methylbenzyl)-1H-pyrazole,-   1-(2,3-Difluorobenzyl)-3-[4-difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole,-   1-(4-Aminobenzyl)-3-[4-difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole,-   1-(2,3-Difluorobenzyl)-3-[4-methoxy-3-(3S)-tetrahydrofuranyloxyphenyl]-1H-pyrazole,-   1-Cyclohexylmethyl-3-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole,-   3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(3-phenpropyl)-1H-pyrazole,-   3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(4-pyridylmethyl)-1H-pyrazole,-   1-Ethylsulfonyl-3-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole,-   3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(1-propyl)-1H-pyrazole,-   1-Benzylsulfonyl-3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole,-   3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(2-pyridylmethyl)-1H-pyrazole,-   3-(3-Benzyloxy-4-methoxyphenyl)-1-(2,3-difluorobenzyl)-1H-pyrazole,-   3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-[N-(1,2,3,4-tetrahydroisoquinolyl)carbonylmethyl]-1H-pyrazole,-   1-[N-(7-Azaindolyl)carbonylmethyl]-3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole,-   1-(2,3-Difluorobenzyl)-3-[3-(2,3-difluorobenzyloxy)-4-methoxyphenyl]-1H-pyrazole,-   1-(2,3-Difluorobenzyl)-3-(3-hydroxy-4-methoxyphenyl)-1H-pyrazole,-   3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(2-phenethyl)-1H-pyrazole,-   2-{3-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}-1-phenyl-1-ethanone,-   1-Benzyl-3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole,-   1-Cyclopentyl-3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole,-   3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-[2-(6-methylpyridyl)]-1H-pyrazole,-   1-Cyclohexylmethyl-3-(4-methoxy-3-(3S)-tetrahydrofuranyloxyphenyl)-1H-pyrazole,-   3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(methylsulfonylbenzyl)-1H-pyrazole,-   3-(2-Acetyl-7-methoxybenzofuran-4-yl)-1-(2,3-difluorobenzyl)-1H-pyrazole,-   3-(2-Acetyl-7-methoxybenzofuran-4-yl)-1-(4-methylsulfonylbenzyl)-1H-pyrazole,-   3-(2-Acetyl-7-methoxybenzofuran-4-yl)-1-(2-methylbenzyl)-1H-pyrazole,-   1-(2-Methoxyethyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole,-   1-(2-Cyclopropylmethoxyethyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole.

Example 31-Cyclohexylmethyl-3-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole

and1-Cyclohexylmethyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole

A solution of3-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole (78 mg, 0.3mmol) in DMF (2 mL) was treated with sodium hydride (60% in oil, 24 mg,0.6 mmol) and stirred at room temperature for three hours. The reactionmixture was then treated with a solution of (bromomethyl)cyclohexane(0.13 mL, 0.9 mmol) in DMF (0.8 mL) and stirred at ambient temperaturefor 16 hours. The mixture was diluted with ethyl acetate (60 mL) andwashed with water (2×20 mL) and brine (1×15 mL), dried (Na₂SO₄) andconcentrated to 250 mg of an oil, which was chromatographed over silicagel using a 10-30% ethyl acetate/hexane gradient. Concentration offractions afforded 92 mg of an oil consisting of a mixture ofregioisomers in a ratio of 3.5:1 as determined by LCMS. The mixture ofregioisomers was taken in 1 mL of acetonitrile/water (3:2 with 0.1%formic acid) and resolved by preparative hplc using a Waters C18, 5 um,30×100 mm column with a flow rate of 45 mL/min. A gradient of 35-80%acetonitrile/water containing 0.1% formic acid over 6 minutes wasemployed and a Waters 2996 PDA detector was utilized to triggercollection at 248 nm. Baseline resolution was achieved with peak Aeluting at 7.61 min and peak B eluting at 8.15 min. Tubes containingeach regioisomer were concentrated on a Genevac HT4 Series II Evaporatorsupplying 14 mg of (peak A; retention time=7.61 minutes)1-cyclohexylmethyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazoleand 54 mg of (peak B; retention time=8.15 minutes)1-cyclohexylmethyl-3-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole,each as colorless oils. Both peaks exhibit [M+H]=357. ¹H NMR for peak A(CDCl₃, 300 MHz) δ 0.80 (m, 2H), 1.1-1.3 (m, 3H), 1.4-1.7 (m, 5H), 1.9(m, 1H), 2.2 (m, 2H), 3.8-4.2 (m, 9H), 4.97 (s, 1H), 6.22 (s, 1H), 6.82(s, 1H), 6.96 (s, 2H), 7.55 (s, 1H).

¹H NMR of peak B (CDCl₃, 300 MHz) δ 0.80 (m, 2H), 1.1-1.3 (m, 3H),1.4-1.7 (m, 5H), 1.9 (m, 1H), 2.2 (m, 2H), 3.8-4.2 (m, 9H), 5.08 (s,1H), 6.44 (s, 1H), 6.9 (d, 1H), 7.35 (m, 3H).

The following compounds were prepared in a similar fashion withdifferent starting materials:

-   1-Cyclohexylmethyl-5-[4-methoxy-3-(3S)-tetrahydrofuranyloxyphenyl]-1H-pyrazole,-   Isopropyl    2-{5-[4-methoxy-3-(3R)-tetrahydrofuranylphenyl]-pyrazol-1-yl}acetate,-   1-(2,3-Difluorobenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranylphenyl]-1H-pyrazole,-   1-(4-fluorobenzyl)-2-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrrole

Example 4 Intermediate B: Synthesis of2-Acetyl-4-bromo-7-methoxybenzofuran

2-Acetyl-7-methoxybenzofuran (1.0 g, 5.3 mmol) was dissolved in glacialacetic acid (29 mL) followed by addition of sodium acetate (1.3 g, 15.8mmol). The reaction was treated dropwise with a solution of bromine(0.26 mL, 5.26 mmol) in glacial acetic acid (10 mL) at room temperaturefollowed by stirring for one hour. The solvent was removed under vacuum.The residue was dissolved in water and extracted three times withdichloromethane. The combined organic extracts were washed with 2%aqueous sodium bicarbonate, dried over sodium sulfate and concentratedunder vacuum. The residue was purified on silica gel using a 50-100%dichloromethane/hexane gradient affording 1.00 g (75%) of the product asa white solid. ¹H NMR (CDCl₃, 300 MHz) δ 7.44 (s, 1H), 7.32 (d, 1H),6.80 (d, 1H), 4.0 (s, 3H), 2.62 (s, 3H).

Intermediate C: Synthesis of4-bromo-7-methoxy-2-[2-methyl-(1,3-dioxolan)-2-yl]benzofuran

A solution of 2-acetyl-4-bromo-7-methoxybenzofuran (0.50 g, 1.86 mmol),5 mL of ethylene glycol, and PPTS (46 mg, 0.186 mmol) was refluxedovernight in benzene (37 mL) using a Dean Stark apparatus. The reactionwas cooled to room temperature, washed with aqueous sodium bicarbonate,dried over sodium sulfate and evaporated under vacuum to afford 293 mg(50%) of 4-bromo-7-methoxy-2-[2-methyl-(1,3-dioxolan)-2-yl]benzofuran asan oil. ¹H NMR (CDCl₃, 300 MHz) δ 7.28 (d, 1H), 6.74 (s, 1H), 6.69 (d,1H), 4.04 (m, 4H), 1.84 (s, 3H).

Intermediate D: Synthesis of7-methoxy-2-[2-methyl-(1,3-dioxolan)-2-yl]-benzofuran-4-carboxaldehyde

4-Bromo-7-methoxy-2-[2-methyl-(1,3-dioxolan)-2-yl]benzofuran (666 mg,2.1 mmol) was dissolved in THF (21 mL), cooled to −60° C. under an argonatmosphere, and t-butyl lithium (2.6 mL, 1.7 M) was added with stirringat −60° C. The mixture was stirred at −60 C. for one hour, DMF (0.82 mL,10.6 mmol) in THF (20mL) was added, and the reaction was stirred atambient temperature overnight. The reaction was poured into aqueoussodium bicarbonate and extracted three times with ethyl acetate. Thecombined extracts were washed once with water, once with brine, anddried over sodium sulfate. Evaporation of the solvent under reducedpressure followed by purification on silica gel using a 10-50% ethylacetate/hexane gradient afforded7-methoxy-2-[2-methyl-(1,3-dioxolan)-2-yl]-benzofuran-4-carboxaldehyde(399 mg; 72%) as an oil. ¹H NMR (CDCl₃, 300 MHz) δ 10.01 (s, 1H), 7.66(d, 1H), 7.45 (s, 1H), 6.88 (d, 1H), 4.08 (m, 7H), 1.84 (s, 3H).

Example 5 Synthesis of 3-(2-Acetyl-7-methoxybenzofuran-4-yl)pyrazole

A suspension of sodium hydride (60% in oil, 174 mg, 4.36 mmol) in THF (5mL) was cooled to 0° C. under argon, and then treated with a solution ofdiethoxyphosphorylacetaldehyde tosylhydrazone (759 mg, 2.2 mmol) in THF(7 mL). After stirring at 0° C. for 30 minutes a solution of7-methoxy-2-(2-methyl-[1,3]dioxolan-2-yl)benzofuran-4-carboxaldehyde(381 mg, 1.45 mmol) in THF (5 mL) was added and the reaction stirred atroom temperature overnight followed by stirring at 65° C. for 5 hours.After cooling to room temperature, the reaction was poured into 5%aqueous NaH₂PO₄ and extracted with ethyl acetate. The extract was washedwith water, washed with brine, dried over Na₂SO₄, and concentrated. Theresidue was chromatographed on silica gel using a 25-50% ethyl acetate/hexane gradient to afford the dioxolane protected pyrazole (306 mg,70%). The masked ketone (306 mg) was taken in 3M HCl in THF (10 mL) andstirred at room temperature for 2 hours. The solution was neutralizedwith sodium bicarbonate and extracted with ethyl acetate three times.The combined extracts were washed with water, washed with brine, driedover sodium sulfate and concentrated under vacuum. The residue waspurified on silica gel using hexane/ethyl acetate (1:1; v/v) to isolate3-(2-Acetyl-7-methoxybenzofuran-4-yl)pyrazole (192 mg, 74%) as a yellowsolid. ¹H NMR (CDCl₃, 300 MHz) δ 8.09 (s, 1H), 7.70 (d, 1H), 7.53 (d,1H), 6.98 (d, 1H), 6.70 (d, 1H), 4.07 (s, 3H), 2.65 (s, 3H).

Example 6 Intermediate E: Synthesis of4-difluoromethoxy-3-hydroxybenzaldehyde

3,4-Dihydroxybenzaldehyde (20 g, 145 mmol), chlorodifluoroacetic acidsodium salt (55.19 g, 362 mmol) and sodium hydroxide (5.50 g, 138 mmol)were stirred in DMF (1200 mL) at 55° C. under nitrogen for 16 hours. ThepH was adjusted to 1.0 by the addition of 10% aqueous HCl followed byextraction with ethyl acetate (3×500 mL). The combined extracts wereevaporated under vacuum. The residue was purified on silica gel using a10-20% ethyl acetate/hexane gradient.4-difluoromethoxy-3-hydroxybenzaldehyde was isolated in 24% yield (6.62g). ¹H NMR (CDCl₃, 400 MHz) δ 6.1 (br s, 1H), 6.48-6.85 (t, 1H OCHF₂),7.26 (d, 1H), 7.44 (d, 1H), 7.55 (s, 1H), 9.91 (s, 1H).

Intermediate F: Synthesis of tert-Butyl2-{3-[4-difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]pyrazol-1-yl}acetate

3-[4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole (199mg, 0.67 mmol) was dissolved in DMF (9 mL). Sodium hydride (60% in oil,54 mg, 1.34 mmol) was added at room temperature and stirred for 1 hourfollowed by addition of tert-butyl bromoacetate (0.30 mL, 2.01 mmol) inDMF (1 mL). The reaction was stirred for 16 hours at room temperature,diluted with ethyl acetate, and washed with water twice and brine once.The solvent was dried over sodium sulfate and concentrated to 500 mg ofa pale yellow oil, which was purified on silica gel using a 20-50% ethylacetate/hexane gradient to afford tert-butyl2-{3-[4-difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]pyrazol-1-yl}acetateas a colorless oil (145 mg, 53%). MS [M+H]=411. ¹H NMR (DMSO 300 MHz) δ1.42 (s, 9H), 2.05 (m, 1H), 2.23 (m, 1H), 3.8-4.0 (m, 4H), 4.98 (s, 2H),5.18 (br s, 1H), 6.78-7.28 (t, 1H OCHF₂), 6.80 (s, 1H), 7.21 (d, 1H),7.38 (d, 1H), 7.45 (s, 1H), 7.77 (s, 1H).

Synthesis of2-{3-[4-difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]pyrazole-1-yl}aceticacid

tert-Butyl2-{3-[4-difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]pyrazol-1-yl}acetate(762 mg, 1.85 mmol) was stirred in dichloromethane (11 mL) and treatedwith trifluoroacetic acid (11 mL) with stirring for 90 minutes. Thesolvent was removed under reduced pressure and partitioned between ethylacetate/water. The organic layer was washed with water three times andbrine once. After drying over sodium sulfate, the solvent was strippedto furnish2-{3-[4-difluoromethoxy-3-(tetrahydrofuryloxy)phenyl]pyrazole-1-yl}aceticacid as a semisolid (657 mg, 100%) MS [M+H]=355. ¹H NMR (CDCl₃ 300 MHz)δ 2.25 (m, 2H), 4.02 (m, 4H), 5.07 (m, 2H), 5.2 (br s, 1H), 6.31-6.81(t, 1H OCHF₂), 6.61 (s, 1H), 7.19-7.28 (m, 3H), 7.29 (s, 1H), 7.52 (s,1H).

2-{3-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)pyrazole-1-yl}aceticacid was synthesized in a similar manner with different startingmaterials.

Example 7 Synthesis of2-{3-[4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}-N-(2,3-difluorophenyl)acetamide

2-{3-[4-difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]pyrazol-1-yl}aceticacid (84 mg, 0.23 mmol) was dissolved in dichloromethane (2 mL), cooledto 5° C. and treated the oxalyl chloride (2M in dichloromethane, 0.13mL, 0.26 mmol) and stirred for 90 minutes. In a separate flask,2,3-difluoroaniline (0.35 mL, 0.35 mmol) in THF (2 mL) was treated withsodium hydride (60% in oil, 22 mg, 0.56 mmol) and stirred for 90minutes. The solvent from the initial flask was removed under reducedpressure. The residue was taken in THF (2 mL), cooled to 5° C. andtreated with the difluoroaniline/hydride suspension followed by stirringat ambient temperature for 16 hours. The solvent was removed undervacuum and the residue was partitioned between ethyl acetate/water. Theorganic layer was washed with water and brine, dried over sodium sulfateand evaporated to afford 57 mg of a brown oil. This was adsorbed onto apreparative thin layer chromatography silica gel plate (20×20 cm, 2000micron) using ethyl acetate/hexane (1:1 v/v) to elute. The product wasisolated from the plate by scraping and suspending the silica gel inethyl acetate following by filtering through a bed of Celite.Evaporation of the solvent afforded2-{3-[4-difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}-N-(2,3-difluorophenyl)acetamideas a white foam (15 mg, 14%) MS [M+H]=446; ¹H NMR (CDCl₃, 300 MHz) δ2.28 (m, 2H), 4.05 (m, 4H), 4.98 (s, 2H), 5.1 (s, 1H), 6.3-6.7 (t, 1HOCHF₂) 6.65 (s, 1H), 6.8 (m, 1H), 6.9 (m, 1H), 7.25 (m, 2H), 7.56 (s,2H) 8.3 (t, 1H), 9.8 (s, 1H).

The following compounds were prepared in a similar fashion withdifferent starting materials:

-   2-{3-[3,4-Bis(difluoromethoxy)-phenyl]-pyrazol-1-yl}-N-(2-methylphenyl)acetamide,-   2-{3-[3,4-Bis(difluoromethoxy)-phenyl]-pyrazol-1-yl}-N-(2,3-difluorophenyl)acetamide,-   1-N-(2-cyanophenyl)-2-{3-[4-difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]pyrazol-1-yl}acetamide,-   2-{3-[4-Difluoromethoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}-N-[2-(6-methylpyridyl)]acetamide.

Example 8 Intermediate G: Methyl 3-ethyl-1H-indazol-6-yl-carboxylate

To a solution of 1.35 g (7.1 mmol) of 3-ethyl-1H-indazol-6-yl-carboxylicacid, [Marfat, A., et al., U.S. Pat. No. 6,262,040], 2.9 mL (71 mmol) ofmethanol, and 0.95 g (7.8 mmol) of DMAP in 60 mL of CH₂Cl₂ was added 1.5g (7.8 mmol) of EDCI-HCl. This mixture was stirred at room temperatureovernight, concentrated and the residue dissolved in 50 mL of ethylacetate. The organic layer was successively washed with 40 mL of 1N HCl,40 mL of water and 40 mL of brine, dried (Na₂SO₄), and concentrated. Theresidue was purified by chromatography over silica gel using a gradientof 35% to 50% ethyl acetate in hexanes over 20 minutes as eluant toyield 860 mg (4.2 mmol) of methyl 3-ethyl-1H-indazol-6-yl-carboxylate.¹H NMR (CDCl₃) δ 11.7 (s, 1H), 8.18 (s, 1H), 7.73 (apparent q, 9.0 Hz,2H), 3.94 (s. 3H), 3.03 (q, 7.5 Hz, 2H), 1.42 (t, 7.5 Hz, 3H).

Intermediate H: Methyl 1-Cyclopentyl-3-ethyl-1H-indazol-6-yl-carboxylate

To a flask containing 337 mg (8.4 mmol) of NaH (60% in mineral oil), 1.7mL (8.4 mmol) of 15-crown-5 and 42 mL of DMF was added 860 mg (4.2 mmol)of methyl 3-ethyl-1H-indazol-6-yl-carboxylate. This mixture was stirredat room temperature for 3 hours and then 1.35 mL (12.6 mmol) ofcyclopentyl bromide was added and the reaction was stirred at roomtemperature overnight. The solvent was removed and the residue wasdissolved in 40 mL ethyl acetate, washed with 30 mL of water and 30 mLof brine, dried (Na₂SO₄), and concentrated. The residue was purified bycolumn chromatography over SiO₂ using a step gradient of 10% ethylacetate in hexanes until the first compound eluted and then 50% ethylacetate in hexanes to provide 662 mg (2.4 mmol) of methyl1-cyclopentyl-3-ethyl-1H-indazol-6-yl-carboxylate as a clear oil alongwith 144 mg (0.53 mmol) methyl2-(cyclopentyl-3-ethyl)-2H-indazol-6-yl-carboxylate as a yellow oil.¹H-NMR (CDCl₃) δ 8.17 (s, 1H), 7.71 (dd, J1=8.4 Hz, J2=6.7 Hz, 2H), 5.0(p, J=7.5 Hz, 1H), 3.97 (s, 3H), 3.00 (q, J=7.5 Hz, 2H), 2.16 (m, 4H),1.92 (m, 2H), 1.74 (m, 2H), 1.39 (t, J=7.6 Hz, 3H).

Intermediate I: 1-Cyclopentyl-3-ethyl-6-hydroxymethyl-1H-indazole

DIBAL (10 mL, 1M in toluene) was slowly added with stirring at −50° C.to a solution of 886 mg (3.25 mmol) of methyl1-cyclopentyl-3-ethyl-1H-indazol-6-yl-carboxylate in 32 mL of CH₂Cl₂.The reaction stirred at −50° C. for 1 hour and was quenched by the slowaddition of 4 mL of MeOH and then, with stirring, poured into asaturated Rochelle's salt and ethyl acetate mixture (60 ml each).Stirring continued at room temperature until both layers were clear. Theorganic layer was separated and the aqueous layer was extracted with3×40 mL of ethyl acetate. The organic fractions were combined, dried(Na₂SO₄), and concentrated. The compound was purified via columnchromatography over SiO₂ using a 1:4 solution of EtOAc in hexanes aseluant to yield 427 mg (1.75 mmol) of1-cyclopentyl-3-ethyl-6-hydroxymethanol-1H-indazole as a clear oil.¹H-NMR (CDCl₃) δ 7.66 (d, J=8.2 Hz, 1H), 7.42 (s, 1H), 7.07 (d, J=8.2Hz), 4.92 (p, J=7.7 Hz, 1H), 4.84 (d, J=5.5 Hz, 2H), 2.99 (q, J=7.6 Hz,2H), 2.15 (m, 4H), 2.04 (m, 2H), 1.73 (m, 2H), 1.38 (t, J=7.6 Hz, 3H).

Intermediate J: 1-Cyclopentyl-3-ethyl-1H-indazol-6-yl-carboxaldehyde

To a solution of 427 mg (1.75 mmol)1-cyclopentyl-3-ethyl-6-hydroxymethanol-1H-indazole in 58 mL of CHCl₃was added 2.1 g (24.1 mmol) of MnO₂. The reaction was stirred at roomtemperature for 6 hours, the solids were removed by filtration and thefiltrate was concentrated. The residue was purified via columnchromatography over SiO₂ using 3% ethyl acetate in hexanes as eluant togive 332 mg (1.37 mmol) of1-cyclopentyl-3-ethyl-1H-indazol-6-yl-carboxaldehyde as a clear oil.¹H-NMR (CDCl₃) δ 10.13 (s, 1H), 7.94 (s. 1H), 7.78 (d, J=8.2 Hz, 1H),7.61 (d, J=8.2 Hz, 1H), 5.02 (p, J=7.4 Hz, 1H), 3.02 (q, J=7.5 Hz, 2H),2.19 (m, 4H), 2.02 (m, 2H), 1.76 (m, 2H), 1.40 (t, J=7.5 Hz, 3H).

3-[(1-Cyclopentyl-3-ethylindazol)-6-yl]-1H-pyrazole

A flask containing 165 mg (4.12 mmol) of NaH (60% in mineral oil) and 4mL of THF was placed under Ar and cooled to 0° C. A solution of 716 mg(2.06 mmol) of diethoxyphosphorylacetaldehydetosylhydrazone in 7 mL ofTHF was added over 5 minutes. The reaction stirred at 0° C. for 30minutes followed by the addition of a solution of 332 mg (1.37 mmol) of1-cyclopentyl-3-ethyl-1H-indazol-6-yl-carboxaldehyde in 4.5 mL THF. Theice bath was removed and the solution was stirred at room temperaturefor 4 hours, and then heated to 65° C. overnight. The reaction mixturewas cooled to room temperature, poured into 50 mL of 5% NaH₂PO₄ andextracted with 3×25 mL of ethyl acetate. The organic layers werecombined, dried over Na₂SO₄, concentrated, and purified by columnchromatography over SiO₂ using a gradient from 10% to 50% ethyl acetatein hexanes over 20 minutes to yield 185 mg (0.66 mmol) of1-cyclopentyl-3-ethyl-6-(1H-pyrazol-3-yl)-1H-indazole as a white foam.¹H-NMR (CDCl₃) δ 7.80 (s, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.65 (s, 1H), 7.5(d, J=8.3 Hz, 1H), 6.7 (s, 1H) 4.90 (p, J=7.5 Hz, 1H), 3.00 (q, J=7.5Hz, 2H), 2.13 (m, 4H), 2.00 (m, 2H), 1.71 (m, 2H), 1.40 (t, J=7.5, 3H).

Example 93-[(1-Cyclopentyl-3-ethylindazol)-6-yl]-1-(2,3-difluorobenzyl)-1H-pyrazole

A solution of 31.8 mg (0.11 mmol) of3-[(1-cyclopentyl-3-ethylindazol)-6-yl]-1H-pyrazole in 1 mL of DMF wasadded to a flask containing 12.9 mg (0.32 mmol) of NaH (60% in mineraloil) and 1 mL of DMF. This was stirred at room temperature for 3 hours.Then, a solution of 43 μL (0.33 mmol) of 2,3-difluorobenzyl bromide in 1mL of DMF was added and the reaction was stirred at room temperatureovernight. The mixture was poured into a mixture of 10 mL of water and10 mL of ethyl acetate. The organic layer was washed with 2×10 mL ofwater and 1×10 mL of brine. The organic layer was then dried overNa₂SO₄, filtered and the solvent was removed under reduced pressure.Purification via column chromatography over 4 g of silica using 5% ethylacetate in hexanes to 10% ethyl acetate in hexanes gradient over 10minutes to give 24 mg (0.06 mmol, 52% yield) of3-[(1-cyclopentyl-3-ethylindazol)-6-yl]-1-(2,3-difluorobenzyl)-1H-pyrazoleas a clear oil. ¹H-NMR (CDCl₃) δ 7.84 (s, 1H), 7.69 (d, J=8.3 Hz, 1H),7.54 (d, J=8.3 Hz, 1H), 7.50 (s, 1H), 7.15-7.04 (m, 3H), 6.68 (s, 1H),5.48 (s, 2H), 4.99 (p, J=7.6 Hz, 1H), 3.01 (q, J=7.4 Hz, 2H), 2.12 (s,4H), 1.98 (s, 2H), 1.75-1.72 (m, 2H), 1.40 (t, 7.4 Hz, 3H).

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   3-[(1-Cyclopentyl-3-ethylindazol)-6-yl]-1-(2,3-difluorophenyl)-1H-pyrazole-   3-[(1-Cyclopentyl-3-ethylindazol)-6-yl])-1-(2-methylbenzyl)-1H-pyrazole-   3-[(1-Cyclopentyl-3-ethylindazol)-6-yl])-1-(4-methylsulfonylbenzyl)-1H-pyrazole-   3-[(1-Cyclopentyl-3-ethylindazol)-6-yl])-1-(2-pyridylmethyl)-1H-pyrazole.

Example 10 Synthesis of2-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1,3-dithiane

4-Methoxy-3-(3R)-tetrahydrofuranyloxybenzaldehyde (8.37 g; 37.6 mmol)was dissolved in dichloromethane (120 mL) followed by addition of1,3-propanedithiol (11.3 mL; 113 mmol) and boron trifluoride etherate(0.6 mL). The reaction mixture became mildly exothermic and turbid.Reaction monitoring by LC-MS showed complete conversion taking place in90 minutes. The reaction was washed with 30 mL of water and 30 mL ofbrine, dried over anhydrous sodium sulfate and concentrated. Triturationof the residue with ether produced a white solid that was collected byfiltration and dried yielding 9.09 g (77%) of2-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1,3-dithiane. ¹H NMR(CDCl₃; 300 MHz) δ 1.85-2.25 (m, 4H); 2.85-2.95 (m, 2H); 3.0-3.1 (m,2H); 3.85 (s, 3H); 3.9-4.1 (m, 4H); 4.95-5.00 (m, 1H); 5.1 (s, 1H); 6.85(d, 1H); 7.00 (d, 1H); 7.05 (d, 1H). ES-MS [M+H]+=313.2

Example 11 Synthesis of2-{2-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1,3-dithian-2-yl}propanol

Solid 2-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1,3-dithiane (2.5g; 8 mmol) was added to an oven-dried flask equipped with a stir bar,septum and an inert gas line. Dry tetrahydrofuran (40 mL) was added andstirred at −40° C. using an acetonitrile/dry ice bath. To the resultingsolution was added n-butyl lithium (2.5M in hexanes; 4.2 mL; 10.4 mmol)via syringe over 15 minutes. After stirring at −40° C. for thirtyminutes, HMPA (1.4 mL; 8 mmol) was injected over two minutes and stirredfor 10 minutes followed by rapid addition of propylene oxide (0.62 mL;8.8 mmol). After stirring at −40° C. for 1 hour, the reaction wasquenched with aqueous ammonium chloride (5 mL), diluted with water (30mL) and extracted with ethyl acetate (70 mL). The organic layer waswashed with 25 mL of water and 25 mL of brine, dried over anhydroussodium sulfate and evaporated to yield 3.5 g of a viscous yellow oil.The crude alcohol was purified by flash chromatography on silica gelusing a 20-60% ethyl acetate/hexane gradient affording the product as acolorless, viscous oil (2.7 g; 91%). ¹H NMR (CDCl₃; 300 MHz) δ 1.1 (d,3H); 2.0-2.5 (m, 7H); 2.75 (m, 4H); 3.8 (s, 3H); 3.9-4.1 (m, 5H); 5.0(m, 1H) 6.9 (d, 1H); 7.5 (m, 2H). ES-MS [M+H]+=371.2

The following compound was synthesized in a similar manner withdifferent starting materials:

-   1-{2-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1,3-dithian-2-yl}butan-2-ol.

Example 12 Synthesis of1-{2-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1,3-dithian-2-yl}propan-2-one

1-{2-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1,3-dithian-2-yl}propan-2-ol(158 mg; 0.42 mmol) was stirred in dichloromethane (5 mL) and treatedwith Dess Martin periodinane (15% solution in dichloromethane; 356 mg;0.84 mmol) and stirred at room temperature for 15 minutes. The solventwas concentrated under reduced pressure and the residue was loaded ontoa column of silica gel and eluted with a 20-60% ethyl acetate/hexanegradient. The product was isolated as an oil (23 mg; 15%). ¹H NMR(CDCl₃; 300 MHz) δ 2.0 (s, 3H); 2.1-2.5 (m, 4H); 2.8 (m, 4H); 3.2 (s,2H); 3.8-4.2 (m, 7H); 5.0 (m, 1H); 6.9 (m, 1H); 7.5 (m, 2H). ES-MS[M+H]+=369.1.

The following compound was synthesized in a similar manner withdifferent starting materials:

-   1-{2-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1,3-dithian-2-yl}butan-2-one.

Alternative Method for Example 12

1-{2-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1,3-dithian-2-yl}propan-2-ol(119 mg; 0.32 mmol) was stirred in dichloromethane (5 mL) and treatedwith Dess-Martin periodinane (15% solution in dichloromethane; 173 mg;0.41 mmol) and stirred at room temperature for 10 minutes. Uponformation of a precipitate, thin layer chromatography analysis usinghexane/ethyl acetate (1:1 v/v) determined the reaction to be complete.The reaction was diluted with dichloromethane (40 mL) and washed with 20mL portions of aqueous sodium bicarbonate and brine. The organic layerwas dried over anhydrous sodium sulfate and evaporated to a crude solid,which was used as such in Example 7.

Example 13 Synthesis of1-(2-Methoxybenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxy-phenyl]-3-methyl-1H-pyrazole

1-{2-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1,3-dithian-2-yl}propan-2-one(115 mg, 0.32 mmol) was reconstituted in toluene (5 mL) and treated with2-methoxybenzyl hydrazine dihydrochloride (144 mg; 0.64 mmol) andmolecular sieves (4A; 500 mg). The reaction was heated at 100° C. fortwo hours and cooled to room temperature. Molecular sieves were removedvia filtration and the filtrate was diluted with ethyl acetate (50 mL),washed with 20 mL portions of water and brine. The organic layer wasdried over anhydrous sodium sulfate and concentrated to an oil. Theproduct was isolated by flash chromatography on silica gel using a20-50% ethyl acetate/hexane gradient to afford 57 mg (45%) of1-(2-methoxybenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H-pyrazoleas a yellow foam. ¹H NMR (CDCl₃; 300 MHz) δ 1.7-2.0 (m, 2H); 2.3 (s,3H); 3.6-4.0 (m, 10H); 4.5 (m, 1H); 5.3 (s, 2H); 6.2 (s, 1H); 6.6 (m,1H); 6.7 (d, 1H): 6.8-7.0 (m, 4H); 7.2 (d, 1H). ES-MS [M+H]+=395.3

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   1-Benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1-phenyl-1H-pyrazole;-   1-Cyclohexyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H-pyrazole;-   1-(1-Butyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H-pyrazole;-   1-(2-Fluorophenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H-pyrazole;-   1-(4-Chlorophenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H-pyrazole;-   3-Ethyl-1-(2-methoxybenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   1-Cyclohexyl-3-ethyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   1-Benzyl-3-ethyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   Ethyl    3-ethyl-[5-(4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-1H-pyrazol-1-yl]acetate;-   1-(2,3-Dimethylphenyl)-3-ethyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   1-(3,4-Dimethylphenyl)-3-ethyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   3-Ethyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(2-methylphenyl)-1H-pyrazole;-   1-(2-Benzothiazolyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H-pyrazole;-   1-(3,4-Dimethylphenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H-pyrazole;-   1-(2,3-Dimethylphenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1-(3-nitrophenyl)-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1-(2-methylphenyl)-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1-(2-phenylethyl)-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1-(4-trifluoromethoxyphenyl)-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1-(2-quinoxalinyl)-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(2-methoxycarbonyl-3-thienyl)-3-methyl-1H-pyrazole;-   1-[2-(6-Fluoropyridyl)]-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1-(2-pyridyl)-1H-pyrazole;-   1-[2-(6-Chloropyridyl)]-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-methyl-1H-pyrazole.

Example 14 Synthesis of1-(3,4-Difluorobenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxy-phenyl]-1H-pyrazole

2-{4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl}-5,5-dimethyl-[1,3,2]dioxaborinane(87 mg, 0.28 mmol), 5-bromo-1-(3,4-difluorobenzyl)-1H-pyrazole (65 mg,0.23 mmol), Pd(PPh₃)₂Cl₂ (37 mg. 0.004 mmol), 2 M Na₂CO₃ aqueous so (0.2mL) and 3 mL of a solvent mixture which consisted of 7:3:2::DME:H₂O:EtOH was placed into a 2.0-5.0 mL Smith Process vial. This wassealed and placed into a Personal Chemistry Emrys Optimizer, stirred for30 seconds, and then heated to 140° C. for 120 seconds. The solution wasthen diluted with 10 mL water and 10 mL ethyl acetate. The organic layerwas separated, dried over Na₂SO₄, filtered and the solvent was removed.Purification by silica gel column chromatography using a gradientelution from 10% to 50% ethyl acetate in hexanes provided 72 mg (79%) of1-(3,4-difluorobenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazoleas a clear oil. ¹H-NMR (CDCl₃, 300 MHz) δ 7.6 (d, 1H), 7.1-6.8 (m, 5H),6.7 (d, 1H), 6.3 (d, 1H), 5.3 (s, 2H), 4.8 (m, 1H), 4.0-3.8 (m, 7H),2.1-2.0 (m, 2H). (M+1)=387.2

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   1-(2,3-Difluorobenzyl)-5-(3,4-dimethoxyphenyl)-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(4-methybenzyl)-1H-pyrazole;-   1-(4-tert-Butylbenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(4-trifluoromethylbenzyl)-1H-pyrazole;-   1-(3,4-Difluorobenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   1-(2-Fluorobenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(3-nitrobenzyl)-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(4-methoxycarbonylbenzyl)-1H-pyrazole;-   1-(3-Fluorobenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   1-(3,5-Dimethoxybenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   1-Benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   1-(3-Methoxybenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   1-(4-Fluorobenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   1-(3,4-Difluorobenzyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole;-   5-(3-Fluoro-4-methoxyphenyl)1-(4-methoxycarbonylbenzyl)-1H-pyrazole;-   1-(2,6-Difluorobenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   1-(4-Fluorobenzyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole; and-   44)    1-(4-fluorobenzyl)-5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-4-methyl-1H-pyrazole    LC/MS (EI) t_(R) 4.2 (Method C), m/z 383.1 (M⁺+1).

Example 15 Synthesis of2-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-5,5-dimethyl-[1,3,2]dioxaborinane

1-Bromo-4-methoxy-3-(3R)-tetrahydrofuranyloxybenzene (500 mg, 1.83 mmol)was added to a flask containing 10 mL of THF. This was cooled to −78° C.under argon and butyllithium (1.5 mL, 2.5 M) was slowly added. Afterstirring at −78° C. for 1.5 hours, trimethyl borate (0.41 mL, 3.7 mmol)in 10 mL of THF was added and the mixture was allowed to warm to roomtemperature overnight. The reaction was quenched by the addition of 20mL of an aqueous saturated solution of NH₄Cl and 20 mL of diethyl ether.The organic layer was washed with 10 mL of water, 10 mL of brine, driedover Na₂SO₄, and concentrated. The residue was dissolved in 18 mL oftoluene and 270 mg of (2.6 mmol) 2,2-dimethylpropane-1,3-diol was added.This was heated to reflux for 4 hours, concentrated, and diluted withhexanes. The insoluble material was washed three times with hexanes. Thecombined organic layer was removed and the product was purified usingcolumn chromatography using a gradient elution from 10% to 100% ethylacetate in hexanes to give 198 mg (35%) of2-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-5,5-dimethyl-[1,3,2]dioxaborinaneas a clear oil. ¹H-NMR (CDCl₃, 300 MHz) δ 7.4 (d, 1H), 7.3 (d, 1H), 6.9(d, 1H), 5.0 (m, 1H), 4.0 (m, 3H), 3.9-3.8 (m, 4H), 3.7 (s, 4H), 2.1 (m,2H), 1.0 (s, 6H).

Example 16 Synthesis of1-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]ethanol

A flask containing 1.7 g (7.5 mmol) of4-methoxy-3-(3R)-tetrahydrofuranyloxybenzaldehyde and 75 mL of THF wascooled to −78° C. under argon and 5.0 mL (3 M) of MeMgCl was slowlyadded. The reaction was stirred at room temperature for 12 hours and wasquenched by the addition of 100 mL of saturated aqueous NH₄Cl. Theaqueous layer was extracted with 3×50 mL of ethyl acetate and thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated. Purification by silica gel column chromatography using agradient elution from 50% to 100% ethyl acetate in hexanes yielded 1.46g (80%) of 1-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-ethanol as awhite solid. ¹H-NMR (CDCl₃, 300 MHz) δ 6.9 (m, 3H), 5.0 (m, 1H), 4.8 (m,1H), 4.0-3.8 (m, 4H), 3.8 (s, 3H), 2.1 (m, 2H), 1.4 (d, 3H).(M-H₂O+1)=221.2

Example 17 Synthesis of1-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]ethanone

Pyridium chlorochromate (2.8 g; 12.3 mmol) was added to a flaskcontaining 1.46 g (6.1 mmol) of1-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]ethanol and 65 mL ofCH₂Cl₂. The mixture was stirred at room temperature for one hour and thesolids were filtered through silica gel, rinsing with 200 mL ethylacetate. The solvent was removed and the residue was purified by columnchromatography using a gradient elution from 20% to 50% ethyl acetate inhexanes to give 1.2 g (83%) of1-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]ethanone as a whitesolid. ¹H-NMR (CDCl₃, 300 MHz) δ 7.5 (d, 1H), 7.4 (d, 1H), 6.8 (d, 1H),4.9 (m, 1H), 4.0-3.9 (m, 3H), 3.8 (m, 4H), 2.5 (s, 3H), 2.1 (m, 2H).(M+1)=237.2.

Example 18 Synthesis of3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-oxopropionaldehyde

A suspension of sodium hydride (60% suspension in mineral oil, 210 mg,5.25 mmol) in 4 mL of THF under argon was treated sequentially with 0.4mL (4.77 mmol) of ethyl formate and a solution of 939 mg (3.98 mmol) of1-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]ethanone in 2 mL of THF.The resulting mixture was stirred at room temperature for 4 hours, andthen acidified with 0.5 N HCl to pH 2 and extracted with 3×10 mL ofethyl acetate. The organic layer was dried over Na₂SO₄, filtered and thesolvent removed. Purification by column chromatography on silica gelusing a gradient elution from 20% to 50% ethyl acetate in hexanesfurnished 218 mg (21%) of3-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-oxopropionaldehyde asa yellow solid. ¹H-NMR (CDCl₃, 300 MHz) δ 8.0 (s, 1H), 7.6-7.5 (m, 2H),7.4 (d, 1H), 6.1 (d, 1H), 5.0 (m, 1H), 4.0 (m, 4H), 3.9 (s, 3H), 2.2 (m,2H). (M+1)=265.2

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   4,4,4-trifluoro-1-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}butane-1,3-dione;-   Ethyl    1-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1,3-dionebutanoate.

Example 19 Synthesis of3-Dimethylamino-1-[4-methoxy-3-(3R)-tetrahydrofuranyloxy-phenyl]propenone

To a solution of 440 mg (1.86 mmol) of1-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-ethanone in 15 mL of DMFwas added 0.30 mL (2.24 mmol) of N,N-dimethylformamide dimethyl acetal.The resulting mixture was heated to 140° C. for 16 hours, then cooled toroom temperature and quenched by the addition of 25 mL of water. Themixture was extracted with 4×25 mL of ethyl acetate and the combinedorganic fractions were dried over Na₂SO₄, filtered and concentrated.Purification by column chromatography over silica gel using a gradientelution from 100% CH₂Cl₂ to 90:10:5:: CH₂Cl₂:MeOH:NH₄OH provided 257 mg(56%) of3-dimethylamino-1-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]propenoneas a yellow oil and 115 mg of the starting ketone. ¹H-NMR (CDCl₃, 300MHz) δ 8.0 (s, 1H), 7.7 (d, 1H), 7.5 (m, 2H), 6.9 (d, 1H), 5.7 (d, 1H),5.1 (m, 1H), 4.0 (m, 3H), 3,9 (s, 4H), 2.9 (s, 3H), 2.8 (s, 3H), 2.2 (m,2H). (M+1)=292.1

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   (2E)-3-(dimethylamino)-1-(3-fluoro-4-methoxyphenyl)prop-2-en-1-one;-   (2E)-1-(3,4-dimethoxyphenyl)-3-(dimethylamino)prop-2-en-1-one;-   (E)-1-(3-Bromo-4-methoxy-phenyl)-3-dimethylamino-propenone;-   (2E)-1-[3,4-bis(difluoromethoxy)phenyl]-3-(dimethylamino)prop-2-en-1-one;-   (2E)-1-[4-(difluoromethoxy)-3-methoxyphenyl]-3-(dimethylamino)prop-2-en-1-one.

Example 20 Synthesis of1-(4-Methoxyphenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxy-phenyl]-1H-pyrazole

3-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-oxopropionaldehyde (45mg, 0.17 mmol), 4-methoxyphenyl hydrazine hydrochloride (36 mg, 0.20mmol) and 1.7 mL of ethanol were combined in a 0.5-2.0 mL Smith ProcessVial. The vial was sealed and heated to 140° C. for 300 seconds using aPersonal Chemistry Emrys Optimizer. The solvent was removed andpurification by silica gel column chromatography using a gradientelution from 20% to 100% ethyl acetate in hexanes provided 40 mg (65%)of1-(4-methoxyphenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazoleas a brown solid. ¹H-NMR (CDCl₃, 300 MHz) δ 7.6 (d, 1H), 7.2 (m, 2H),6.9 (m, 4H), 6.5 (d, 1H), 6.4 (d, 1H), 4.6 (m, 1H), 3.9-3.7 (m, 10H),1.9 (m, 2H). (M+1)=367.2

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   Ethyl    1-Benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole-3-carboxylate;-   1-Benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-trifluoromethyl-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-phenyl-3-trifluoromethyl-1H-pyrazole;-   Ethyl    [5-(4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]acetate;-   [5-(4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]acetic    acid;-   Isopropyl    [5-(4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]acetate;-   1-(3-Fluorobenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-trifluoromethyl-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-phenyl-1H-pyrazole;-   1-Cyclohexyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   Ethyl    1-Benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole-3-carboxylate;-   1-(4-Methoxyphenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(2-phenylethyl)-1H-pyrazole;-   1-(4-Fluorophenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   1-(4-Bromophenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(4-trifluoromethoxyphenyl)-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(2-pyridyl)-1H-pyrazole;-   1-(2-Benzothiazolyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   5-(3-Fluoro-4-methoxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazole;-   1-(2-Methoxyphenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   1-[2-(6-Fluoropyridyl)]-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole.

Example 21 Synthesis of1-(4-Methoxyphenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole

3-Dimethylamino-1-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]propenone,(461 mg, 1.6 mmol), 4-methoxyphenyl hydrazine hydrochloride (304 mg,1.74 mmol), and 5 mL of ethanol were combined in a 2.0-5.0 mL SmithProcess Vial. The vial was sealed and heated to 140° C. for 300 seconds,quenched with 10 mL of water, and the aqueous layer was extracted with3×10 mL of ethyl acetate. The combined organic fractions were dried overNa₂SO₄, filtered and concentrated. Purification by silica gel columnchromatography using a gradient elution from 20% to 100% ethyl acetatein hexanes provided 436 mg (75%) of1-(4-methoxyphenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazoleas a brown solid. ¹H-NMR (CDCl₃, 300 MHz) δ 7.6 (d, 1H), 7.2 (m, 2H),6.9 (m, 4H), 6.5 (d, 1H), 6.4 (d, 1H), 4.6 (m, 1H), 3.9-3.7 (m, 10H),1.9 (m, 2H). (M+1)=367.2

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   1-Benzyl-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole;-   Ethyl    2-{5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]pyrazol-1-yl}acetate;-   5-(3,4-Dimethoxyphenyl)-1-(4-fluorobenzyl)-1H-pyrazole;-   5-(3,4-Dimethoxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazole;-   3-[(1-Cyclopentyl-3-ethylindazol)-6-yl]-1-(4-carboxyphenyl)-1H-pyrazole;-   3-[(1-Cyclopentyl-3-ethylindazol)-6-yl]-1-(4-methoxyphenyl)-1H-pyrazole;-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-[4-(4-morpholinyl)phenyl]-1H-pyrazole;-   1-(4-Carboxyphenyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   1)    1-cyclopentyl-3-ethyl-6-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-1H-indazole;    LC/MS (EI) t_(R) 5.55 (Method C), m/z 387.3 (M⁺+1)-   2)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzoic    acid; LC/MS (EI) t_(R) 4.82 (Method C), m/z 401.2 (M⁺+1)-   3)    1-cyclopentyl-3-ethyl-6-(1-pyridin-2-yl-1H-pyrazol-5-yl)-1H-indazole;    LC/MS (EI) t_(R) 4.79 (Method C), m/z 358.3 (M⁺+1)-   4)    1-cyclopentyl-6-[1-(3,4-difluorophenyl)-1H-pyrazol-5-yl]-3-ethyl-1H-indazole;    LC/MS (EI) t_(R) 5.95 (Method C), m/z 393.3 (M⁺+1)-   5) 6-(1-benzyl-1H-pyrazol-5-yl)-1-cyclopentyl-3-ethyl-1H-indazole;    LC/MS (EI) t_(R) 5.92 (Method C), m/z 371.3 (M⁺+1)-   6)    1-cyclopentyl-3-ethyl-6-(1-pyridin-4-yl-1H-pyrazol-5-yl)-1H-indazole;    LC/MS (EI) t_(R) 3.81 (Method C), m/z 358.2 (M⁺+1)-   7)    1-cyclopentyl-3-ethyl-6-(1-piperidin-4-yl-1H-pyrazol-5-yl)-1H-indazole;    LC/MS (EI) t_(R) 2.24 (Method C), m/z 364.2 (M⁺+1)-   13)    1-cyclopentyl-3-ethyl-6-{1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-5-yl}-1H-indazole;    LC/MS (EI) t_(R) 7.99 (Method E), m/z 441.2 (M⁺+1)-   14)    1-cyclopentyl-3-ethyl-6-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-1H-indazole;    LC/MS (EI) t_(R) 6.65 (Method E), m/z 375.2 (M⁺+1)-   15)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzonitrile;    LC/MS (EI) t_(R) 6.32 (Method E), m/z 382.2 (M⁺+1)-   16)    6-[1-(4-chlorophenyl)-1H-pyrazol-5-yl]-1-cyclopentyl-3-ethyl-1H-indazole;    LC/MS (EI) t_(R) 391.2/393.1 (Method E), m/z 7.76 (M⁺+1)-   17)    1-cyclopentyl-3-ethyl-6-[1-(4-methylphenyl)-1H-pyrazol-5-yl]-1H-indazole,    LC/MS (EI) t_(R) 7.14 (Method E), m/z 371.2 (M⁺+1)-   18)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzenesulfonamide,    LC/MS (EI) t_(R) 4.31 (Method C), m/z 436.1 (M⁺+1)-   22)    1-cyclopentyl-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole;    LC/MS (EI) t_(R) 4.83 (Method C), m/z 435.2 (M⁺+1) and-   26)    1-cyclopentyl-6-{1-[4-(difluoromethoxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1H-indazole    LC/MS (EI) t_(R) 4.94 (Method C), m/z 423.1 (M⁺+1)-   29)    4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzoic    acid-   30)    5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole;    LC/MS (EI) t_(R) 3.2 (Method C), m/z 415.2 (M⁺+1)-   31)    2-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)-1,3-thiazole;    LC/MS (EI) t_(R) 3.39 (Method C), m/z 344.2 (M⁺+1)-   32) 1-benzyl-5-(3,4-dimethoxyphenyl)-1H-pyrazole; LC/MS (EI) t_(R)    3.81 (Method C), m/z 295.3 (M⁺+1)-   33)    2-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzoic    acid; LC/MS (EI) t_(R) 2.85 (Method C), m/z 381.1 (M⁺+1)-   34)    3-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzoic    acid; LC/MS (EI) t_(R) 3.18 (Method C), m/z 381.2 (M⁺+1)-   40) 4-[5-(3,4-dimethoxyphenyl)-1H-pyrazol-1-yl]pyridine; LC/MS (EI)    t_(R) 2.11 (Method C), m/z 282.2 (M⁺+1)-   41)    4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1yl)pyridine;    LC/MS (EI) t_(R) 2.2 (Method C), m/z 338.1 (M⁺+1)-   42)    4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)piperidine;    LC/MS (EI) t_(R) 2.07 (Method C), m/z 344.2 (M⁺+1)-   45) 5-(3-Bromo-4-methoxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazole;    LC/MS (EI) t_(R) 4.51 (Method C), m/z 359.0/361.0 (M⁺+1)-   51)    1-Isobutyl-5-(4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl)-1H-pyrazole;    LC/MS (EI) t_(R) 3.8, m/z 317.2 (M⁺+1)-   52)    5-[3,4-bis(difluoromethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazole;    LC/MS (EI) t_(R) 4.28 (Method C), m/z 383 (M⁺+1)-   56)    5-[4-(difluoromethoxy)-3-methoxyphenyl]-1-(4-methoxyphenyl)-1H-pyrazole,    LC/MS (EI) t_(R) 4.31, m/z 347.1 (M⁺+1)-   71)    4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzenesulfonamide,    LC/MS (EI) t_(R) 3.29, m/z 416.1 (M⁺+1)-   72)    4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzonitrile,    LC/MS (EI) t_(R) 3.98, m/z 362.1 (M⁺+1)-   82) 5-[3-(benzyloxy)-4-methoxyphenyl]-1-(4-fluorophenyl)-1H-pyrazole    (prepared in 94% yield),-   89)    5-[3,4-bis(difluoromethoxy)phenyl]-1-[4-(difluoromethoxy)phenyl]-1H-pyrazole;    LC/MS (EI) t_(R) 4.79 (Method C), m/z 419.1 (M⁺+1)-   90) 4-[5-(3-ethyl-2-methyl-2H-indazol-6-yl)-1H-pyrazol-1-yl]benzoic    acid, LC/MS (EI) t_(R) 3.24 (Method C), m/z 347.2 (M⁺+1)-   91)    1,3-diethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,    LC/MS (EI) t_(R) 3.99 (Method C), m/z 395.2 (M⁺+1)-   92)    1-(cyclopropylmethyl)-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,    LC/MS (EI) t_(R) 4.24 (Method C), m/z 421.2 (M⁺+1)-   93)    3-ethyl-1-isopropyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,    LC/MS (EI) t_(R) 4.31 (Method C), m/z 409.2 (M⁺+1)-   94)    3-ethyl-1-(2-methoxyethyl)-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,    LC/MS (EI) t_(R) 3.81 (Method C), m/z 425.2 (M⁺+1)-   96)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N,N-dimethylbenzenesulfonamide,    LC/MS (EI) t_(R) 5.63 (Method C), m/z 464.2 (M⁺+1)-   97)    1-(ethoxymethyl)-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,    LC/MS (EI) t_(R) 4.29 (Method C), m/z 425.1 (M⁺+1)-   113)    2-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]quinoxaline,    LC/MS (EI) t_(R) 4.78 (Method E), m/z 409.2 (M⁺+1)-   114)    1-{4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenyl}-N-methylmethanesulfonamide,    LC/MS (EI) t_(R) 3.12 (Method E), m/z 464.2 (M⁺+1)-   115)    1-(3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazol-1-yl)-2-methylpropan-2-ol,    LC/MS (EI) t_(R) 3.67 (Method A), m/z 439.2 (M⁺+1)-   122)    1-cyclopropyl-3-ethyl-6-(1-isopropyl-1H-pyrazol-5-yl)-1H-indazole,    LC/MS (EI) t_(R) 4.64 (Method A), m/z 295.2 (M⁺+1)-   123) 1-cyclopropyl-3-ethyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-indazole,    LC/MS (EI) t_(R) 4.04 (Method A), m/z 267.1 (M⁺+1)-   124) 1-cyclopropyl-3-ethyl-6-(1H-pyrazol-5-yl)-1H-indazole, LC/MS    (EI) t_(R) 3.78 (Method A), m/z 253.2 (M⁺+1)-   125) 1-cyclopropyl-3-ethyl-6-(1-ethyl-1H-pyrazol-5-yl)-1H-indazole,    LC/MS (EI) t_(R) 4.36 (Method A), m/z 281.2 (M⁺+1)-   126)    1-cyclopropyl-3-ethyl-6-(1-pyridin-4-yl-1H-pyrazol-5-yl)-1H-indazole,    LC/MS (EI) t_(R) 3.27 (Method A), m/z 330.2 (M⁺+1)-   127)    2-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]quinoxaline,    LC/MS (EI) t_(R) 5.18 (Method A), m/z 381.1(M⁺+1)-   130)    1-{4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenyl}-N-methylmethanesulfonamide,    LC/MS (EI) t_(R) 3.98 (Method A), m/z 436.1 (M⁺+1)-   131)    1-cyclopropyl-3-ethyl-6-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]-1H-indazole,    LC/MS (EI) t_(R) 4.15 (Method A), m/z 337.2 (M⁺+1)-   132)    1-cyclopropyl-3-ethyl-6-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl]-1H-indazole,    LC/MS (EI) t_(R) 4.34 (Method A), m/z 337.2 (M⁺+1)-   133)    1-cyclopropyl-6-[1-(1,1-dioxidotetrahydro-3-thienyl)-1H-pyrazol-5-yl]-3-ethyl-1H-indazole,    LC/MS (EI) t_(R) 4.45 (Method A), m/z 371.2 (M⁺+1)-   134)    6-(1-cyclopentyl-1H-pyrazol-5-yl)-1-cyclopropyl-3-ethyl-1H-indazole,    LC/MS (EI) t_(R) 5.30 (Method A), m/z 371.2 (M⁺+1)-   136)    1-cyclopropyl-3-ethyl-6-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazol-5-yl]-1H-indazole,    LC/MS (EI) t_(R) 4.86 (Method A), m/z 392.3 (M⁺+1)-   137)    6-{1-[3-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-1-cyclopropyl-3-ethyl-1H-indazole,    LC/MS (EI) t_(R) 7.0 (Method E), m/z 435.2 (M⁺+1)-   139)    3-ethyl-1-isopropyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-pyrazolo[3,4-b]pyridine,    LC/MS (EI) t_(R) 5.09 (Method A), m/z 410.2 (M⁺+1)-   140)    2-{3-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenoxy}ethanol,    LC/MS (EI) t_(R) 2.99 (Method E), m/z 389.3 (M⁺+1)-   141)    6-{1-[4-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-1-cyclopropyl-3-ethyl-1H-indazole,    LC/MS (EI) t_(R) 6.74 (Method E), m/z 435.3 (M⁺+1)-   142)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,    LC/MS (EI) t_(R) 4.42 (Method A), m/z 452.2 (M⁺+1)-   144)    (4-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenyl)methanol,    LC/MS (EI) t_(R) 4.09 (Method A), m/z 404.2 (M⁺+1)-   147)    1-cyclopropyl-3-ethyl-6-[1-(3-methoxyphenyl)-1H-pyrazol-5-yl]-1H-indazole,    LC/MS (EI) t_(R) 4.38 (Method E), m/z 359.2 (M⁺+1)-   149)    1-cyclopropyl-3-ethyl-6-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-1H-indazole,    LC/MS (EI) t_(R) 4.5 (Method E), m/z 359.2 (M⁺+1)-   150)    1-cyclopropyl-3-ethyl-6-(1-pyrimidin-2-yl-1H-pyrazol-5-yl)-1H-indazole,    LC/MS (EI) t_(R) 3.97 (Method A), m/z 331.2 (M⁺+1)-   151)    3-ethyl-1-(2-methoxypyridin-4-yl)-6-(1-pyrimidin-2-yl-1H-pyrazol-5-yl)-1H-indazole    LC/MS (EI) t_(R) 4.67 (Method A), m/z 398.2 (M⁺+1)-   152)    1-[4-(difluoromethoxy)phenyl]-5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazole,    LC/MS (EI) t_(R) 3.94 (Method C), m/z 419.1 (M⁺+1)-   153)    1-cyclopentyl-3-ethyl-6-[1-(pyridin-4-ylmethyl)-1H-pyrazol-5-yl]-1H-indazole,    LC/MS (EI) t_(R) 3.17 (Method C), m/z 372.3 (M⁺+1)-   154)    4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]pyridine,    LC/MS (EI) t_(R) 1.84 (Method C), m/z 352.2 (M⁺+1)-   155) 4-[5-(3-ethyl-1-methyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzoic    acid, LC/MS (EI) t_(R) 3.56 (Method C), m/z 3417.2 (M⁺+1)-   156)    4-[5-(3-ethyl-1-methyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzenesulfonamide,    LC/MS (EI) t_(R) 3.27 (Method C), m/z 382.2 (M⁺+1)-   157)    3-ethyl-1-methyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,    LC/MS (EI) t_(R) 3.56 (Method C), m/z 381.3 (M⁺+1)-   158)    4-[5-(3-ethyl-1-methyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzonitrile,    LC/MS (EI) t_(R) 4.15 (Method C), m/z 328.2 (M⁺+1)-   159)    4-[5-(3-ethyl-2-methyl-2H-indazol-6-yl)-1H-pyrazol-1-yl]benzenesulfonamide,    LC/MS (EI) t_(R) 2.97 (Method C), m/z 382.2 (M⁺+1)-   160)    3-ethyl-2-methyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-2H-indazole,    LC/MS (EI) t_(R) 3.22 (Method C), m/z 381.3 (M⁺+1)-   161)    4-[5-(3-ethyl-2-methyl-2H-indazol-6-yl)-1H-pyrazol-1-yl]benzonitrile,    LC/MS (EI) t_(R) 3.65 (Method C), m/z 328.2 (M⁺+1)-   162)    6-{1-[4-(difluoromethoxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,    LC/MS (EI) t_(R) 440.2 (Method E), m/z 4.56 (M⁺+1)-   163)    3-ethyl-6-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,    LC/MS (EI) t_(R) 4.26 (Method E), m/z 392.2 (M⁺+1)-   164)    3-ethyl-6-(1-pyridin-4-yl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,    LC/MS (EI) t_(R)×2.57 (Method E), m/z 375.2 (M⁺+1)-   165)    3-ethyl-6-(1-phenyl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,    LC/MS (EI) t_(R) 4.2 (Method E), m/z 374.3 (M⁺+1)-   166)    3-ethyl-6-(1-pyrimidin-2-yl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,    LC/MS (EI) t_(R) 2.55 (Method E), m/z 376.2 (M⁺+1)-   167)    3-ethyl-6-[1-(3-fluorophenyl)-1H-pyrazol-5-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,    LC/MS (EI) t_(R) 4.65 (Method E), m/z 392.2 (M⁺+1)-   168)    3-ethyl-6-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,    LC/MS (EI) t_(R) 4.07 (Method E), m/z 404.2 (M⁺+1)-   169)    3-ethyl-6-[1-(3-methoxyphenyl)-1H-pyrazol-5-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,    LC/MS (EI) t_(R) 4.17 (Method E), m/z 404.2 (M⁺+1)-   170)    6-{1-[4-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,    LC/MS (EI) t_(R) 6.59 (Method E), m/z 480.3 (M⁺+1)-   171)    6-{1-[3-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,    LC/MS (EI) t_(R) 6.5 (Method E), m/z 480.3 (M⁺+1).

Example 22 Synthesis of5-(3-Cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazole

A solution of 5-chloro-3-methyl-1-phenyl-1H-pyrazole (61.8 mg, 0.32mmol) in 5 mL of THF was cooled to −78° C. and t-butyllithium (0.47 mL,1.7 M in heptane) was slowly added. The mixture was stirred at −78° C.for 1.5 hours and then zinc chloride (1.56 mL, 0.5 M) was added andafter stirring at −78° C. for 15 minutes was warmed to room temperature.A solution containing 4-bromo-2-cyclopentyloxy-1-methoxybenzene (148 mg,0.54 mmol) and Pd(PPh₃)₄ (35 mg, 0.03 mmol) in 1 ML of THF was added andthe reaction was heated to 60° C. for 12 hours. The mixture was dilutedwith 20 mL of ethyl acetate and the organic layer was washed with 10 mLof a saturated ammonium chloride solution, 20 mL of water and 20 mL ofbrine. The organic layer was dried over sodium sulfate, filtered andconcentrated. Purification by silica gel column chromatography using agradient elution from 20% to 50% ethyl acetate in hexanes yielded 31 mgof 5-(3-cyclopentyloxy-4-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazole.¹H-NMR (CDCl₃, 300 MHz) δ 7.3 (m, 5H), 6.8 (m, 2H), 6.6 (d, 1H), 6.3 (s,1H), 4.4 (m, 1H), 3.8 (s, 3H). 2.4 (s, 3H), 1.7-1.5 (m, 8H). (M+1)=349.1

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1-(4-trifluoromethoxybenzyl)-1H-pyrazole.

Example 23 Synthesis of{5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-trifluoromethyl-1H-pyrazol-1-yl}aceticacid

{5-[4-Methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-trifluoromethyl-pyrazol-1-yl}-aceticacid ethyl ester (239 mg, 0.58 mmol) was dissolved in 5 mL of a solutionmade of 35 g KOH in 25 mL water. The reaction mixture was diluted with100 mL of methanol, heated to 100° C. for 1 hour, and cooled to roomtemperature. Acidification with 1N HCl resulted in the formation of awhite solid, which was isolated by filtration to give 100 mg of{5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-trifluoromethyl-1H-pyrazol-1-yl}aceticacid. ¹H-NMR (CDCl₃, 300 MHz) δ 6.9 (s, 2H), 6.8 (s, 1H), 6.5 (s, 1H),4.9 (m, 4H), 4.0 (s, 4H), 3.9 (s, 3H), 2.2 (s, 2H). (M+1)

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   1-Benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole-3-carboxylic    acid;-   1-(4-Carboxybenzyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole;-   1-(4-Carboxybenzyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole.

Example 24 Synthesis ofN-(3-Fluorophenyl)-2-{5-[4-methoxy-3-(3R)-tetrahydrofuranyloxy-phenyl]-3-trifluoromethylpyrazol-1-yl}acetamide

A solution of{5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-trifluoromethyl-1H-pyrazol-1-yl}aceticacid (50 mg, 0.13 mmol) in 2 mL of DMF was treated with HOBt (33 mg,0.22 mmol), diisopropylethylamine (38 uL, 0.22 mmol), 3-fluoroaniline(21 uL, 0.22 mmol), and EDCI (38 uL, 0.22 mmol) and was then stirred atroom temperature for 16 h. The reaction was diluted with 10 mL of ethylacetate; the organic layer was separated and sequentially washed with 10mL of water, 10 mL of 1N HCl, 10 mL of saturated NaHCO₃, and 10 mL ofbrine, dried (Na₂SO₄) and concentrated. Purification by silica gelcolumn chromatography using 10% ethyl acetate in hexanes provided 21 mgofN-(3-fluorophenyl)-2-{5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-3-trifluoromethyl-pyrazol-1-yl}acetamideas a white solid.

¹H-NMR (CDCl₃, 300 MHz) δ 8.6 (s, 1H), 7.5 (d, 1H), 7.3 (m, 1H), 7.1-7.0(m, 3H), 7.0-6.8 (m, 2H), 6.6 (s, 1H), 5.0 (m, 1H), 4.9 (s, 2H), 4.0-3.9(m, 7H), 2.2 (m, 2H).

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   N-Cyclopropyl-2-{5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}acetamide;-   N-Isopropyl-2-{5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}acetamide;-   N-Phenyl-2-{5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}acetamide;-   N,N-Diethyl-2-{5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-pyrazol-1-yl}acetamide.

Example 25 Synthesis of2-{1-Benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazol-3-yl}propan-2-ol(A) and1-{1-Benzyl-5-[4-methoxy-3-(3R)-tetrahydro-furanyloxyphenyl]-1H-pyrazol-3-yl}ethanone(B)

A solution of1-benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole-3-carboxylicacid ethyl ester (144 mg, 0.34 mmol) in 3 mL of THF was cooled to −78°C. under argon and MeMgCl (0.34 mL, 3.0 M) was added slowly. Thesolution was warmed to room temperature over 2 hours and then 10 mL ofsaturated aqueous NH₄Cl was added. The mixture was extracted with 3×10mL of ethyl acetate and the combined organic fractions were dried overNa₂SO₄, filtered and concentrated. Purification by silica gel columnchromatography using a gradient elution from 20% to 50% ethyl acetate inhexanes yielded 55 mg of2-{1-benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazol-3-yl}propan-2-olA as a clear oil and 20 mg of1-{1-benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazol-3-yl}ethanoneB as a clear oil. ¹H-NMR (CDCl₃, 300 MHz) A δ 7.3 (m, 3H), 7.0 (d, 2H),6.9 (m, 2H), 6.6 (d, 1H), 6.2 (s, 1H), 5.3 (s, 2H), 4.6 (m, 1H), 4.0-3.7(m, 7H), 2.0 (m, 2H), 1.6 (s, 6H). ¹H-NMR (CDCl₃, 300 MHz) B δ 7.3 (m,3H), 7.0 (d, 2H), 6.9 (s, 2H), 6.8 (s, 1H), 6.6 (s, 1H), 5.3 (s, 2H),4.6 (m, 1H), 4.0-3.7 (m, 7H), 2.6 (s, 3H), 1.9 (m, 2H), (M+1) A 409.2 B393.2.

The following compound was synthesized in a similar manner withdifferent starting materials:

-   145)    2-(4-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenyl)propan-2-ol,    LC/MS (EI) t_(R) 4.73 (Method A), m/z 432.2 (M⁺+1)

Example 26 Synthesis of{1-Benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazol-3-yl}methanol

A solution of1-benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole-3-carboxylicacid ethyl ester (62 mg, 0.15 mmol) in 3 mL THF was cooled to 0° C.under argon. LAH (0.25 mL, 1M) was added and after stirring for 1 hourthe reaction was quenched by the slow addition of 5 mL of methanol and 5mL of 0.1 N HCl. The aqueous layer was extracted with 2×10 mL of ethylacetate and the combined organic fractions were concentrated.Purification by silica gel column chromatography using a gradientelution from 50% to 100% ethyl acetate in hexanes yielded 20 mg of{1-Benzyl-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazol-3-yl}methanolas a clear oil. ¹H-NMR (CDCl₃, 300 MHz) δ 7.3 (m, 3H), 7.0 (d, 2H), 6.9(m, 2H), 6.6 (d, 1H), 6.3 (s, 1H), 5.3 (s, 2H), 4.7 (s, 2H), 4.6 (m,1H), 3.9-3.7 (m, 7H), 2.5 (s, 1H), 2.0-1.4 (m, 2H). (M+1)=381.2

The following compounds were synthesized in a similar manner withdifferent starting materials:

1-(2-Hydroxyethyl)-5-[4-methoxy-3-(3R)-tetrahydrofuranyloxyphenyl]-1H-pyrazole.

Example 27 Synthesis of 5-Bromo-1-(2,6-difluorobenzyl)-1H-pyrazole Step1: 2-(2,6-Difluorobenzyl)-1-hydroxy-1H-pyrazole

1-Hydroxypyrazole (49.3 mg, 0.59 mmol, 1.0 eq) was mixed with 165.8 mg(0.80 mmol, 1.36 eq) of 2,6-difluorobenzyl bromide in ˜1-2 mL ofanhydrous CHCl₃ under argon. The mixture was heated at 80° C. for 18 hunder inert atmosphere in a sealed flask without condenser. The residuewas partitioned between 37 weight percent aqueous HCl and toluene. Theaqueous layer was collected and the toluene fraction extracted againwith 37 weight percent aqueous HCl. The combined aqueous HCL fractionswere neutralized with 5N aqueous NaOH to pH˜11-12 and thenback-extracted with 3×30 mL of CHCl₃. The organic layers were combined,washed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to yield 86.3 mg (70.1% yield) of2-(2,6-difluorobenzyl)-1-hydroxy-1H-pyrazole as a tan brown solid. ¹HNMR (CDCl₃ 300 MHz) δ 7.37 (m, 1H), 7.18 (d, 1H), 6.95 (t, 2H), 6.85 (d,1H), 6.11 (t, 1H), 5.43 (s, 2.00 H). LC/MS (ES) M+1=211.2

Step 2: 5-Bromo-1-(2,6-difluorobenzyl)-1H-pyrazole

2-(2,6-Difluorobenzyl)-1-hydroxy-1H-pyrazole (81.2 mg, 0.386 mmol, 1.0eq) and 5 ml of anhydrous CHCl₃ were combined in a flame-dried 25 mLround-bottom flask under argon and cooled in an ice/water bath. Asolution of POBr₃ (398.1 mg, 1.39 mmol, 3.60 eq) in 3 mL of CHCl₃ wasadded using a syringe in aliquots over an hour period with stirring. Thereaction solution was warmed to room temperature and stirred for 16hours. The CHCl₃ was removed in vacuo and the resulting orange mixturewas neutralized with saturated aqueous NaHCO₃ and extracted with 3×30 mLof diethyl ether. The combined ether fractions were washed with brine,dried over Na₂SO₄ and concentrated in vacuo to yield 101.5 mg (96.7%yield) of 5-bromo-1-(2,6-difluorobenzyl)-1H-pyrazole as a hygroscopicorange-tan colored solid. ¹H NMR (CDCl₃ 300 MHz) δ 7.51 (d, 1H), 7.34(m, 1H), 6.94 (t, 2H), 6.29 (d, 1H), 5.50 (s, 2H). LC/MS (ES) M+1=273.1,275.1

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   5-Bromo-1-(4-trifluoromethoxybenzyl)-1H-pyrazole;-   5-Bromo-1-(2,3-difluorobenzyl)-1H-pyrazole;-   5-Bromo-1-(4-methylbenzyl)-1H-pyrazole;-   5-Bromo-1-(4-tert-butylbenzyl)-1H-pyrazole;-   5-Bromo-1-(4-trifluoromethylbenzyl)-1H-pyrazole;-   5-Bromo-1-(3,4-difluorobenzyl)-1H-pyrazole;-   5-Bromo-1-(2-fluorobenzyl)-1H-pyrazole;-   5-Bromo-1-(3-nitrobenzyl)-1H-pyrazole;-   5-Bromo-1-(4-methoxycarbonylbenzyl)-1H-pyrazole;-   5-Bromo-1-(3-fluorobenzyl)-1H-pyrazole;-   5-Bromo-1-(3,5-dimethoxybenzyl)-1H-pyrazole;-   1-Benzyl-5-bromo-1H-pyrazole;-   5-Bromo-1-(3-methoxybenzyl)-1H-pyrazole;-   5-Bromo-1-(4-fluorobenzyl)-1H-pyrazole;-   5-Bromo-1-(2,6-difluorobenzyl)-1H-pyrazole.

Example 28 76)5-[4-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]-1H-tetrazole

4-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)benzonitrile(40.0 mg, 0.111 mmol), sodium azide (35.82 mg, 0.5510 mmol), ammoniumchloride (29.5 mg, 0.552 mmol), and 1 mL of N,N-dimethylformamide weremixed in a 500 mL flask and heated under an atmosphere of N₂ at 110° C.for 6 hours. The mixture was cooled to room temperature and poured into5 mL of ice cold 3.0 M aqueous HCl. The precipitate was collected byvacuum filtration and washed with several portions of water. The solidwas dried in vacuo overnight to give 20 mg (0.044 mmol, 40%) of5-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-yl)phenyl]-1H-tetrazoleas a yellow solid. LC/MS (EI) t_(R) 3.52, m/z 405.1 (M⁺+1) ¹H NMR (CDCl₃300 MHz) δ 2.0 (m, 2H); 3.7-3.9 (m, 4H); 3.9 (s, 3H); 4.8 (m, 1H); 6.6(s, 2H); 7.0 (d, 1H); 7.1 (d, 1H); 7.4 (d, 2H); 7.8 (d, 2H); 7.8 (s,1H).

The following compound was synthesized in a similar manner withdifferent starting materials:

-   21)    1-cyclopentyl-3-ethyl-6-{1-[4-(1H-tetrazol-5-yl)phenyl]-1H-pyrazol-5-yl}-1H-indazole    (prepared in 49% yield).

Example 29 43)1-[4-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]piperazine

Into a vial was added tert-butyl4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]piperazine-1-carboxylate(20.0 mg, 0.0384 mmol) and 1 mL of a 20% (v/v) solution of TFA inCH₂Cl₂. The reaction was stirred at room temperature for 1 hour and thenthe solvent was removed under reduced pressure. The residue wasdissolved in 10 mL of ethyl acetate and washed once with 10 mL ofsaturated aqueous NaHCO₃. The organic layer was then dried over sodiumsulfate and concentrated under reduced pressure to give 13 mg (0.0309mmol, 80%) of1-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]piperazineas a yellow oil. LC/MS (EI) t_(R) 2.02 (Method C), m/z 421.2 (M⁺+1). ¹HNMR (CDCl₃ 300 MHz) δ 1.9 (m, 4H); 3.0 (d, 4H); 3.1 (d, 4H); 3.7-3.9 (m,3H); 3.8 (s, 3H); 4.6 (m, 1H); 6.4 (s, 1H); 6.5 (s, 1H); 6.8 (m, 3H);7.0 (d, 1H); 7.2 (d, 2H); 7.7 (s, 1H).

Example 30 25)4-[5-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N,N-diethylbenzamide

Into a 1-neck round-bottom flask was added4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzoicacid (50.0 mg, 0.125 mmol), 2 mL of N,N-dimethylformamide, diethylamine(0.00913 g, 0.125 mmol), HATU (47.4 mg, 0.125 mmol) andN,N-diisopropylethylamine (43.5 uL, 0.250 mmol). The reaction wasstirred for 3 days at room temperature, concentrated under reducedpressure, and purified by preparative HPLC (UV detection) to give 33 mg(0.0725 mmol, 58%) of4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N,N-diethylbenzamideas a clear oil. LC/MS (EI) t_(R) 5.26 (Method C), m/z 456.1 (M⁺+1). ¹HNMR (CDCl₃ 300 MHz) δ 1.0-1.2 (m, 5H); 1.3 (t, 3H); 1.7-1.9 (m, 5H); 2.0(m, 4H); 3.0 (q, 2H); 3.1 (br s, 2H); 3.4 (br s, 2H); 4.8 (m, 1H); 6.6(s, 1H); 6.9 (d, 1H); 7.2 (m, 5H); 7.5 (d, 1H); 7.7 (s, 1H).

Example 31 Synthesis of(2E)-1-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-3-(dimethylamino)prop-2-en-1-one

Under argon 1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)ethanone (815 mg,3.18 mmol), N,N-dimethylformamide dimethyl acetal (0.634 mL, 4.77 mmol)and 30 mL of N,N-dimethylformamide were combined and warmed to 140° C.overnight. The reaction mixture was poured into 50 mL of water andextracted with 3×75 mL of ethyl acetate. The combined organic fractionswere dried over sodium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography over silica geleluting with CH₂Cl₂ for 10 minutes and then with a linear gradient over30 minutes to 100% of [10% MeOH in CH₂Cl₂ with 0.1% NH₄OH] to give 954mg (3.18 mmol, 96%) of(2E)-1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-3-(dimethylamino)prop-2-en-1-oneas a yellow oil. LCMS m/z 312.2 (M⁺+1).

Example 32 37)N-[(4-Methoxyphenyl)sulfonyl]4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]benzamide

Into a vial was added4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]benzoicacid (50.0 mg, 0.127 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (30.2 mg,0.158 mmol), 4-dimethylaminopyridine (19.3 mg, 0.158 mmol),4-methoxybenzenesulphonamide (29.5 mg, 0.158 mmol) and 2 mL of methylenechloride. The reaction was stirred overnight at room temperature, pouredinto 10 mL of water and 10 mL of ethyl acetate and the pH of the aqueouslayer was adjusted to pH˜6 by adding saturated aqueous NaHCO₃. Theorganic layer was dried over sodium sulfate, filtered and approximately1 g of silica gel was added and the mixture was evaporated to drynessunder reduced pressure. The residue was purified by columnchromatography on silica gel using a gradient elution going from 0% to10% methanol in dichloromethane over 20 minutes to giveN-[(4-methoxyphenyl)sulfonyl]-4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]benzamide(53 mg, 74%) as a yellow foam. LC/MS (EI) t_(R) 5.22 (Method C), m/z564.2 (M⁺+1). ¹H NMR (CDCl₃ 300 MHz) δ 1.8-2.0 (m, 2H); 2.6 (br s, 2H);3.6 (m, 2H); 3.8 (m, 2H); 3.9 (s, 3H); 4.4 (br s, 1H); 5.2 (s, 2H); 6.3(s, 1H); 6.4 (s, 1H); 6.9 (m, 3H); 7.2-7.6 (m, 3H); 7.7 (t, 2H); 7.8 (d,2H); 7.9 (d, 2H).

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   36)    4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]-N-(phenylsulfonyl)benzamide;    LC/MS (EI) t_(R) 534.5 (Method C), m/z 2.7 (M⁺+1)-   38)    N-[(4-fluorophenyl)sulfonyl]-4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]benzamide;    LC/MS (EI) t_(R) 5.45 (Method C), m/z 552.1 (M⁺+1)-   19)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N-(methylsulfonyl)benzamide;    LC/MS (EI) t_(R) 5.04, m/z 478.2 (M⁺+1)-   20)    4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N-(ethylsulfonyl)benzamide    LC/MS (EI) t_(R) 5.19, m/z 492.2 (M⁺+1).

Example 33 53)2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethylphenylcarbamate

2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethanol(20 mg, 0.066 mmol), 0.50 mL of methylene chloride, phenyl isocyanate(30 uL, 0.28 mmol) were combined in a test tube and stirred for 3 daysat room temperature. Trisamine scavenger resin (Argonaut P/N 800228,˜3-5 equiv) was added and the mixture was stirred for 2-3 hours,filtered through an Acro Disc (0.45 um) filter and concentrated to yield29.3 mg of a light yellow solid. The crude product was recrystallizedfrom 0.5 mL of methanol to give2-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethylphenylcarbamate (14.5 mg, 52%) as white needle-like crystals. LC/MS (EI)t_(R) 4.6 (Method C), m/z 424.2 (M⁺+1). ¹H NMR (CDCl₃ 300 MHz) δ 2.1-2.2(m, 2H); 3.8 (s, 3H); 3.8-4.0 (m, 2H); 4.0-4.2 (m, 2H); 4.5 (m, 2H); 4.6(m, 2H); 4.9 (m, 1H); 6.3 (s, 1H); 6.7 (m, 1H); 6.9 (s, 2H); 7.0-7.1 (m,2H); 7.3 (m, 3H); 7.6 (s, 1H).

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   48)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(4-fluorophenyl)carbamate;    LC/MS (EI) t_(R) 4.0, m/z 442.1 (M⁺+1)-   49)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    benzylcarbamate; LC/MS (EI) t_(R) 3.9, m/z 438.1 (M⁺+1)-   50)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    1-methylpropylcarbamate; LC/MS (EI) t_(R) 3.5, m/z 404.2 (M⁺+1)-   54)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    propylcarbamate; LC/MS (EI) t_(R) 3.4 (Method C), m/z 390.2 (M⁺+1)-   55)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    (2-fluorophenyl)carbamate; LC/MS (EI) t_(R) 3.6, m/z 440.2 (M⁺+1)-   57)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(4-methoxyphenyl)carbamate;    LC/MS (EI) t_(R) 3.6, m/z 454.2 (M⁺+1)-   58)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(3-fluorophenyl)carbamate;    LC/MS (EI) t_(R) 3.8, m/z 442.1 (M⁺+1)-   59)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(4-chlorophenyl)carbamate;    LC/MS (EI) t_(R) 4.1, m/z 458.1 (M⁺+1)-   69)    2-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(2-furylmethyl)carbamate;    LC/MS (EI) t_(R) 3.4, m/z 428.2 (M⁺+1)-   70)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(4-methylphenyl)carbamate;    LC/MS (EI) t_(R) 3.9, m/z 438.2 (M⁺+1)-   73)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(cyclopentyl)carbamate;    LC/MS (EI) t_(R) 3.7, m/z 416.2 (M⁺+1)-   77)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(4-cyanophenyl)carbamate;    LC/MS (EI) t_(R) 3.6, m/z 449.1 (M⁺+1)-   78)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    [2-(2-thienyl)ethyl]carbamate; LC/MS (EI) t_(R) 3.6, m/z 458.1    (M⁺+1)-   79)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(3,5-dimethylisoxazol-4-yl)carbamate;    LC/MS (EI) t_(R) 3.1, m/z 443.1 (M⁺+1)-   80)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    3-thienylcarbamate; LC/MS (EI) t_(R) 3.7, m/z 430.1 (M⁺+1)-   75)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl    2-thienylcarbamate LC/MS (EI) t_(R) 3.11 (Method C), m/z 430.1    (M⁺+1)-   83)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(3,4-dichlorophenyl)carbamate;    LC/MS (EI) t_(R) 4.5, m/z 492.1 (M⁺+1) and-   84)    2-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)ethyl(3,4-difluorophenyl)carbamate    LC/MS (EI) t_(R) 4.0, m/z 460.2 (M⁺+1).

Example 34 67)2-Methoxy-5-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]pyridine

1-(4-Bromophenyl)-5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazole(52.0 mg, 0.125 mmol), bis(triphenylphosphine)palladium(II) chloride (20mg, 0.02 mmol), 0.1 mL of 2.00 M aqueous sodium carbonate, 2 mL of amixture of DME, water and ethanol in a 7:3:2 ratio, and2-methoxy-5-pyridineboronic acid (21.1 mg, 0.138 mmol) were combined ina 2.0-5.0 mL Smith Process vial. This was sealed and placed into aPersonal Chemistry Emrys Optimizer, stirred for 30 seconds, and thenheated to 140° C. for 300 seconds. Upon cooling, 10 mL of water and 10mL of ethyl acetate were added and the organic layer was separated,dried over sodium sulfate, filtered and approximately 1 g of silica gelwas added and the mixture was evaporated to dryness under reducedpressure. The residue was purified by column chromatography on silicagel eluting with 10% ethyl acetate in hexanes for 3 minutes, then with alinear gradient to 100% ethyl acetate over 18 minutes and then with 100%ethyl acetate for an additional 10 minutes to give2-methoxy-5-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]pyridine(45 mg, 82%) as a yellow oil. LC/MS (EI) t_(R) 4.3 (Method C), m/z 444.1(M⁺+1). ¹H NMR (CDCl₃ 300 MHz) δ 1.9 (m, 2H); 3.7-3.9 (m, 4H); 3.9 (s,3H); 4.0 (s, 3H); 4.8 (m, 1H) 6.5 (s, 1H); 6.6 (s, 1H); 6.9 (m, 2H); 7.0(d, 2H); 7.4 (d, 2H); 7.5 (d, 2H); 7.8 (t, 2H); 8.3 (2, 1H).

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   8)    1-cyclopentyl-3-ethyl-6-[1-(4-pyrimidin-5-ylphenyl)-1H-pyrazol-5-yl]-1H-indazole;    LC/MS (EI) t_(R) 4.98 (Method C), m/z 435.2 (M⁺+1)-   9)    1-cyclopentyl-3-ethyl-6-{1-[4-(1H-pyrazol-4-yl)phenyl]-1H-pyrazol-5-yl}-1H-indazole;    LC/MS (EI) t_(R) 4.71 (Method C), m/z 423.1 (M⁺+1)-   10)    1-cyclopentyl-3-ethyl-6-{1-[4-(1H-pyrrol-2-yl)phenyl]-1H-pyrazol-5-yl}-1H-indazole;    LC/MS (EI) t_(R) 6.0 (Method C), m/z 422.2 (M⁺+1)-   11)    1-cyclopentyl-3-ethyl-6-[1-(4-pyridin-3-ylphenyl)-1H-pyrazol-5-yl]-1H-indazole;    LC/MS (EI) t_(R) 4.56 (Method C), m/z 434.2 (M⁺+1)-   35)    1-[4-(3-furyl)phenyl]-5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazole;    LC/MS (EI) t_(R) 4.07 (Method C), m/z 403.2 (M⁺+1)-   46)    5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1-[4-(1H-pyrrol-2-yl)phenyl]-1H-pyrazole;    LC/MS (EI) t_(R) 4.03 (Method C), m/z 402.1 (M⁺+1)-   47)    3-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]pyridine;    LC/MS (EI) t_(R) 2.57 (Method C), m/z 414.1 (M⁺+1)-   60)    1-benzyl-4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]-1H-pyrazole;    LC/MS (EI) t_(R) 4.39 (Method C), m/z 493.2 (M⁺+1)-   61)    2-fluoro-5-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]pyridine,-   62)    5-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]pyrimidine;    LC/MS (EI) t_(R) 3.29 (Method C), m/z 415.1 (M⁺+1)-   63)    N-[4′-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)biphenyl-2-yl]acetamide;    LC/MS (EI) t_(R) 3.61 (Method C), m/z 470.1 (M⁺+1)-   64)    4′-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)biphenyl-2-carboxamide;    LC/MS (EI) t_(R) 3.36 (Method C), m/z 456.1 (M⁺+1)-   65)    N-[4′-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)biphenyl-3-yl]acetamide;    LC/MS (EI) t_(R) 3.89 (Method C), m/z 470.1 (M⁺+1)-   66)    3-fluoro-4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]pyridine;    LC/MS (EI) t_(R) 3.7 (Method C), m/z 432.1 (M⁺+1)and-   68)    4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]-3,5-dimethylisoxazole    LC/MS (EI) t_(R) 4.3 (Method C), m/z 432.2 (M⁺+1).

Example 35 23)4-[5-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N-methoxy-N-methylbenzamide

To a solution of4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzoicacid (100.0 mg, 0.250 mmol) in 1.2 mL of methylene chloride under atatmosphere of argon at 0° C. was added N,N-carbonyldiimidazole (48.2 mg,0.297 mmol) with stirring. After 30 minutes N,O-dimethylhydroxylaminehydrochloride (59.9 mg, 0.614 mmol) was added and the resultantsuspension was warmed to room temperature, stirred for 24 hours and then10 mL of water and 10 mL of ethyl acetate were added. The organic layerwas separated, washed with 10 mL of 1N NaOH, 10 mL of water, 10 mL ofbrine, dried over sodium sulfate, and filtered. Approximately 2 g ofsilica gel were added and the mixture was evaporated to dryness underreduced pressure. The residue was purified by column chromatography oversilica gel eluting with a linear gradient from 10% ethyl acetate inhexanes to 50% ethyl acetate in hexanes over 20 minutes to yield4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N-methoxy-N-methylbenzamide(55 mg, 50%) as a white solid.

Example 36 74)4-(5-{4-Methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)aniline

Into a 1-neck round-bottom flask was addedN-(diphenylmethylene)-4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)aniline(52.0 mg, 0.101 mmol), 1.0 mL of tetrahydrofuran, and 0.1 mL of 2.0 Maqueous HCl. The reaction was stirred at room temperature for 2 hoursand 10 mL of 0.5 N HCl in water and 10 mL of a 2:1 mixture of hexanesand ethyl acetate were added. The clear aqueous layer was basified with1 N NaOH and extracted with 3×10 mL of ethyl acetate. The combinedorganic fractions were dried over sodium sulfate and concentrated underreduced pressure to yield4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)aniline(28 mg, 79%) as a tan solid. LC/MS (EI) t_(R) 3.11 (Method C), m/z 352.1(M⁺+1)

Example 37 12)4-[5-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzamide

4-[5-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzoicacid (7 mg, 0.02 mmol), PYBOP (14 mg, 0.026 mmol), 1.0 mL ofN,N-dimethylformamide, 1-hydroxybenzotriazole (3.5 mg, 0.026 mmol),N,N-diisopropylethylamine (12 uL, 0.070 mmol) and ammonium chloride (1.9mg, 0.035 mmol) were combined in a 1-neck round-bottom flask and stirredat room temperature for two hours. The mixture was treated with 10 mL ofsaturated aqueous NaHCO₃ and 10 mL of ethyl acetate. The organic layerwas separated, dried over sodium sulfate, filtered and approximately 500mg of silica gel was added. The mixture was evaporated to dryness underreduced pressure and the residue was purified by column chromatographyover silica gel eluting with a gradient of 10% ethyl acetate in hexanesfor 5 minutes and then increasing linearly to 100% ethyl acetate at 25minutes to yield4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzamide(5 mg, 62%) as a white solid. LC/MS (EI) t_(R) 4.09 (Method C), m/z400.2 (M⁺+1). ¹H NMR (CDCl₃ 300 MHz) δ 1.4 (t, 3H); 1.6 (m, 2H); 1.8 (m,2H); 2.1 (m, 4H); 3.0 (q, 2H); 4.8 (m, 1H); 5.7 (br s, 1H); 6.0 (br s,1H); 6.6 (s, 1H); 6.9 (d, 1H); 7.3-7.5 (m, 3H); 7.6 (d, 1H); 7.8 (m,3H).

Example 38 Synthesis of 1-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)ethanol

A solution of 1-cyclopentyl-3-ethyl-1H-indazole-6-carboxaldehyde (1.00g, 4.13 mmol) in 40 mL of tetrahydrofuran under argon was cooled to −78°C. and with stirring treated with 3 mL of 3 M methylmagnesium chloridein tetrahydrofuran. The reaction was stirred at −78° C. for 1 hour,slowly warmed to room temperature overnight and then quenched byaddition of 100 mL of saturated aqueous NH₄Cl. The mixture was extractedwith 3×50 mL of ethyl acetate and the combined organic fractions weredried over sodium sulfate and concentrated to give1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)ethanol as a yellow solid. Thecrude residue was not purified but used as such in the next step.

Example 39 Synthesis of1-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)ethanone

Into a 1-neck round-bottom flask was added1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)ethanol (1.06 g, 4.10 mmol),pyridinium chlorochromate (1.77 g, 8.20 mmol) and 40 mL of methylenechloride. The reaction was stirred at room temperature for 1 hour,filtered through Celite, and rinsed with 200 mL of ethyl acetate.Approximately 20 g of silica gel were added and the mixture wasevaporated to dryness under reduced pressure. The residue was purifiedby column chromatography over silica gel eluting with 20% ethyl acetatein hexanes to yield 1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)ethanone(809 mg, 77%).

Example 40 24)1-4-[5-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenylethanone

4-[5-(1-Cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]-N-methoxy-N-methylbenzamide(66 mg, 0.15 mmol) and 2 mL of tetrahydrofuran were combined in aone-necked round-bottom, placed under an atmosphere of argon, cooled to−78° C., and 0.10 mL of 3 M methylmagnesium chloride in tetrahydrofuranwas slowly added. The reaction was stirred at −78° C. for 30 minutes,warmed to 0° C. for 60 minutes and another 0.2 mL of 3 M methylmagnesiumchloride in THF was added. The reaction was allowed to stir at 0° C. for30 minutes and 10 mL of saturated aqueous NH₄Cl was added and themixture was allowed to warm to room temperature. The aqueous layer wasextracted with 20 mL of ethyl acetate and the separated organic layerwas dried over sodium sulfate, filtered and concentrated under reducedpressure to yield1-4-[5-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenylethanone(35 mg, 59%) as a white solid. LC/MS (EI) t_(R) 5.68 (Method C), m/z399.1 (M⁺+1). ¹H NMR (CDCl₃ 300 MHz) δ 1.3 (t, 3H); 1.6 (m, 2H); 1.9 (m,2H); 2.0 (m, 4H); 2.5 (s, 3H); 3.0 (t, 2H); 4.8 (m, 1H); 6.5 (s, 1H);6.8 (d, 1H); 7.2 (s, 1H); 7.3 (d, 2H); 7.4 (d, 1H); 7.7 (s, 1H); 7.6 (d,2H).

Example 41 81) 5-[1-(4-Fluorophenyl)-1H-pyrazol-5-yl]-2-methoxyphenol

Into a 1-neck round-bottom flask was added5-[3-(benzyloxy)-4-methoxyphenyl]-1-(4-fluorophenyl)-1H-pyrazole (3.5 g,9.3 mmol) and 100 mL of ethanol. The flask was flushed with nitrogen for10 minutes and 350 mg of 10% Pd/C was added. The reaction was thenstirred under one atmosphere of hydrogen at room temperature overnight.The reaction was degassed under reduced pressure, flushed with argon for5 minutes, filtered through Celite and concentrated to yield 2.6 g (98%)of 5-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-2-methoxyphenol as a grey oil.m/z 285.0 (M⁺+1). ¹H NMR (CDCl₃ 300 MHz) δ 3.9 (s, 3H); 5.6 (s, 1H); 6.4(s, 1H); 6.8 (d, 1H); 7.0 (d, 2H); 7.4 (d, 2H); 7.6 (m, 2H); 7.7 (s,1H).

Example 42 39) Tert-butyl4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]piperazine-1-carboxylate

Into a 1-neck round-bottom flask was added2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (4.74 mg, 0.0120mmol),1-(4-bromophenyl)-5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazole(50.0 mg, 0.120 mmol), tert-butyl 1-piperazinecarboxylate (26.9 mg,0.144 mmol) and tris(dibenzylideneacetone)dipalladium(0) (11.0 mg,0.0120 mmol). The reaction was placed under an atmosphere of argon, 0.4mL of 1.00 M lithium bis(trimethylsilyl)amide in tetrahydrofuran wasadded and the mixture was heated to 65° C. for 16 hours. After coolingto room temperature, 30 mL of saturated aqueous NH₄Cl solution was addedand the aqueous layer was extracted with 30 mL ethyl acetate. Theseparated organic layer was dried over sodium sulfate, filtered, andapproximately 1 g silica gel was added and the mixture was evaporated todryness under reduced pressure. The residue was purified by columnchromatography on silica gel eluting with 20% ethyl acetate in hexanesto yield tert-butyl4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]piperazine-1-carboxylate(21 mg, 34%) as a yellow oil. LC/MS (EI) t_(R) 4.62 (Method C), m/z521.3 (M⁺+1). ¹H NMR (CDCl₃ 300 MHz) δ 1.5 (s, 9H); 1.9 (m, 2H); 3.1 (m,4H); 3.6 (m, 4H); 3.7-3.9 (m, 4H); 3.9 (s, 3H); 4.6 (m, 1H); 6.4 (s,1H); 6.6 (s, 1H); 6.9-7.1 (m, 4H); 7.2 (d, 2H); 7.6 (s, 1H).

The following compound was synthesized in a similar manner withdifferent starting materials:

-   27)    4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]morpholine    LC/MS (EI) t_(R) 3.45 (Method C), m/z 422.2 (M⁺+1).

Example 43 Synthesis of4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-1-yl)methyl]benzoicacid

Into a 1-neck round-bottom flask was added methyl4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]benzoate(330 mg, 0.808 mmol), 5 mL of 1,4-dioxane, 20 mL of water and 8 mL of 2M aqueous sodium hydroxide. The reaction was heated at 90° C. for 1.5hours, acidified with 1N HCl until pH˜3 and extracted with 3×20 mLCH₂Cl₂. The combined organic fractions were dried over sodium sulfate,filtered and concentrated under reduced pressure to yield4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]benzoicacid (260 mg, 81%) as a brown solid. LCMS M+1=395.2

The following compound was synthesized in a similar manner withdifferent starting materials:

-   28) 4-{[5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]methyl}benzoic    acid LC/MS (EI) t_(R) 3.49 (Method C), m/z 327.2 (M⁺+1).

Example 44 85) 5-(3,4-Dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazole

5-[1-(4-Fluorophenyl)-1H-pyrazol-5-yl]-2-methoxyphenol (50.0 mg, 0.176mmol), 5 mL of N,N-dimethylformamide and methyl iodide (16.4 uL, 0.264mmol) were combined in a vial and stirred at room temperature overnight.An additional 0.5 mL of methyl iodide was added and stirring continuedfor 2 days at room temperature and then 10 mL of ethyl acetate and 10 mLof water were added. The organic layer was separated, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel eluting with agradient of 10% ethyl acetate in hexanes to 50% ethyl acetate in hexanesover 20 minutes to give5-(3,4-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazole (25 mg, 48%) as awhite solid. LC/MS (EI) t_(R) 4.14, m/z 299.1 (M⁺+1). ¹H NMR (CDCl₃ 300MHz) δ 3.7 (s, 3H); 3.9 (s, 3H); 6.5 (s, 1H); 6.7 (s, 1H); 7.0 (s, 2H);7.1 (m, 2H); 7.3 (m, 2H); 7.7 (s, 1H).

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   86) 5-(3-ethoxy-4-methoxyphenyl)-1-(4-fluorophenyl)-1H-pyrazole;    LC/MS (EI) t_(R) 4.41, m/z 313.2 (M⁺+1)-   87)    5-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-1-(4-fluorophenyl)-1H-pyrazole;    LC/MS (EI) t_(R) 4.69, m/z 339.1 (M⁺+1)-   88)    5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-(4-fluorophenyl)-1H-pyrazole    LC/MS (EI) t_(R) 5.11 (Method C), m/z 353.2 (M⁺+1)

Example 45 Synthesis of 1-[4-(Difluoromethoxy)-3-hydroxyphenyl]ethanoneand 1-[3,4-bis(difluoromethoxy)phenyl]ethanone

A solution of 1-(3,4-dihydroxyphenyl)ethan-1-one (2.00 g, 13.1 mmol) in200 mL of N,N-dimethylformamide was treated with potassium hydroxide(6.64 g, 118 mmol) and the reaction was stirred at room temperature forone hour. The reaction mixture was cooled with a dry ice/acetone bath tomaintain an internal temperature <25° C. and chlorodifluoroacetic acid(5.57 mL, 65.7 mmol) was slowly added and the reaction was then allowedto warn to room temperature for one hour. The reaction was heated to 65°C. overnight and after cooling to room temperature, the reaction wasdiluted with 400 mL of water and extracted with 3×150 mL methyl t-butylether making sure the water layer was pH˜3. The organic layer wasextracted with 3×100 mL of 1 N NaOH. To obtain1-[3,4-bis(difluoromethoxy)phenyl]ethanone, the separated organic layerwas dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel eluting with a gradient of 10% ethyl acetate in hexanes to 100%ethyl acetate over 30 minutes to yield1-[3,4-bis(difluoromethoxy)phenyl]ethanone (531 mg, 16%).

To obtain 1-[4-(difluoromethoxy)-3-hydroxyphenyl]ethanone, the NaOHsolution was acidified with 1N HCl and extracted with 3×100 mL diethylether. The combined organic fractions were dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel eluting with a gradientof 10% ethyl acetate in hexanes to 100% ethyl acetate over 30 minutes toyield 1-[4-(difluoromethoxy)-3-hydroxyphenyl]ethanone (314 mg, 12%).

Example 46 Synthesis of(2E)-1-[4-(Difluoromethoxy)-3-methoxyphenyl]-3-(dimethylamino)prop-2-en-1-one

Into a 1-necked flask were added1-[4-(difluoromethoxy)-3-hydroxyphenyl]ethanone (0.317 g, 1.57 mmol), 16mL of N,N-dimethylformamide, and N,N-dimethylformamide dimethy acetal(0.25 mL, 1.9 mmol). The mixture was heated to 140° C. overnight andafter cooling to room temperature, poured into 50 mL water and extracted3×50 mL ethyl acetate. The combined organic fractions were dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel eluting witha gradient of 50% ethyl acetate in hexanes to 100% ethyl acetate over 30minutes to give(2E)-1-[4-(difluoromethoxy)-3-methoxyphenyl]-3-(dimethylamino)prop-2-en-1-one(51 mg, 0.188 mmol) as a yellow oil.

Example 47 Synthesis of3-Ethyl-N-methoxy-N-methyl-1H-indazole-6-carboxamide

3-ethyl-1H-indazole-6-carboxylic acid (3.9 g, 0.020 mol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (4.3 g,0.022 mol) and 4-dimethylaminopyridine (3.11 g, 0.0254 mol),N,O-dimethylhydroxylamin hydrochloride (2.8 g, 0.028 mol) were dissolvedin methylene chloride (200 mL) and N,N-dimethylformamide (20 mL) and thesolution stirred at room temperature for one hour. The resulting mixturewas poured in iced water. The aqueous layer was removed, and extractedwith ethyl acetate (2×50 mL). The combined organics were washed with 1 NHCl, 2N NaOH, water, and brine, then dried. The solvent was removed invacuo, and the residue was purified by column chromatography on silicagel eluting with a gradient of 50% ethyl acetate in hexanes to 100%ethyl acetate over 30 minutes to give 1.6 g (33%) of3-ethyl-N-methoxy-N-methyl-1H-indazole-6-carboxamide.

Example 48 Synthesis of3-Ethyl-N-methoxy-N-methyl-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-6-carboxamide

NaH (1.3 g, 60% dispersion in mineral oil, 0.033 mol) andtetrahydrofuran (223 mL) were mixed in a 1-necked flask and cooled to 0°C. To this was added dropwise a mixture of3-ethyl-N-methoxy-N-methyl-1H-indazole-6-carboxamide (2.6 g, 0.011 mol)in tetrahydrofuran (60 mL), and the mixture was stirred at 0° C. for 1hour. [β-(Trimethylsilyl)ethoxy]methyl chloride (2.4 mL, 0.013 mol) wasthen added and the reaction mixture was allowed to warm to roomtemperature. The resulting mixture was partitioned between water (50 mL)and ethyl acetate (50 mL). The layers were separated and the organicswere washed with brine (25 mL), dried (sodium sulfate) and concentratedin vacuo to afford 4.0 g (quantitative yield) of3-ethyl-N-methoxy-N-methyl-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-indazole-6-carboxamide,which was used without further purification.

Example 49 Synthesis of1-(3-Ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-6-yl)ethanone

Methylmagnesium chloride (7.7 mL, 3M in tetrahydrofuran) was addeddropwise at −78° C. under an atmosphere of argon to a solution of3-Ethyl-N-methoxy-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-6-carboxamide(4.0 g, 0.011 mol) in tetrahydrofuran (114 mL). The resulting mixturewas allowed to warm slowly to room temperature. The reaction was thenquenched by the addition of a saturated solution of ammonium chloride.Ethyl acetate (150 mL) and water (100 mL) were then added, and theorganic layer was separated, washed with water and with brine, and thendried (sodium sulfate). After filtration, the solvent was concentrated,and the residue was purified by column chromatography on silica gel,eluting with a gradient of 50% ethyl acetate in hexanes to 100% ethylacetate over 30 minutes, to give 3.5 g (quantitative yield) of1-(3-Ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-6-yl)ethanone.¹H NMR (CDCl₃) δ 0.0 (m, 1H), 1.0 (t, 3H), 1.1-1.4 (m, 2H), 2.7 (s, 3H),2.9-3.1 (m, 2H), 3.5 (1, 2H), 5.7 (s, 2H), 7.5 (m, 2H), 8.0 (s, 1H).

Example 50 Synthesis of(2E)-3-(Dimethylamino)-1-(3-Ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-6-yl)prop-2-en-1-one

Under an atmosphere of argon, 1,1-Dimethoxy-N,N-dimethylmethanamine (4.4mL, 0.033 mol) and1-(3-Ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-6-yl)ethanone(3.5 g, 0.011 mol) were mixed in N,N-dimethylformamide (110 mL) and theresulting mixture was heated at 140° C. for 16 hours. After cooling toroom temperature, water (250 mL) and ethyl acetate (250 mL) were added,the layers were separated, and the product was extracted with ethylacetate (3×100 mL). The combined organic layers were washed with waterand brine, dried (sodium sulfate), and the volatiles were removed invacuo to afford 4.1 g (quantitative yield) of(2E)-3-(dimethylamino)-1-(3-Ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-6-yl)prop-2-en-1-one,which was used without further purification.

Example 51 Synthesis of6-{1-[3-(Benzyloxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1H-indazole

(2E)-3-(dimethylamino)-1-(3-Ethyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-6-yl)prop-2-en-1-one(256 mg, 0.685 mmol) and 3-benzyloxyphenylhydrazine hydrochloride (270mg, 1.1 mmol) were dissolved in ethanol (4 mL) in a 10 mL sealed tube.The mixture was subjected to microwave radiation (300 watts, 160° C.)for 5 minutes. The solvent was removed and the residue was extractedwith ethyl acetate, then washed with water and brine. Removal ofvolatiles provided a tan solid, which was purified by columnchromatography on silica gel, eluting with a 10-50% hexane/ethyl acetategradient over 10 minutes (flow rate 20 mL/min), to give 160 mg (59%) of6-{1-[3-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1H-indazole. ¹H NMR(CDCl₃) δ 1.4 (t, 3H), 3.0 (q, 2H), 5.0 (s, 2H), 6.6 (d, 1H), 6,8 (d,1H), 6.9 (d, 1H), 7.1 (m, 2H), 7.2 (t, 1H), 7.3 (m, 5H), 7.6 (d, 1H),7.8 (m, 1H), 9.7 (br s, 1H).

Example 52 99)3-Ethyl-2-(1-ethylpropyl)-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-2H-indazole

3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole(100 mg, 0.27 mmol), 3-bromopentane (70 mg, 0.46 mmol), potassiumcarbonate (45 mg, 0.33 mmol) and N,N-dimethylformamide (2 mL) were addedto a 1-necked flask. The mixture was heated to 60° C. for 6 hours, thenslowly cooled to room temperature and stirred for a further 48 hours. Afurther equivalent of 3-bromopentane (41 mg, 0.27 mmol) was then added,and the reaction was heated to 120° C. After cooling to roomtemperature, water and ethyl acetate were added. The product wasextracted once with ethyl acetate, and washed with water and brine. Thecombined organics were dried, and filtered and concentrated. The residewas purified by column chromatography on silica gel (eluting using 50%ethyl acetate in hexanes for 10 minutes and then a linear gradient to100% ethyl acetate in hexanes at 20 minutes) to give 4.4 mg (3.7%) of3-ethyl-2-(1-ethylpropyl)-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-2H-indazole.LC/MS (EI) t_(R) 4.36 (Method C), m/z 437.1 (M⁺+1), ¹H NMR (CDCl₃) δ 0.6(t, 3H), 1.4 (t, 2H), 1.8 (m, 2H), 1.9 (m, 2H), 3.0 (m, 6H), 4.0 (m,1H), 6.5 (s, 1H), 7.0 (d, 1H), 7.1 (s, 1H), 7.5 (d, 2H), 7.7 (m, 1H),7.8 (s, 1H), 7.8 (d, 2H). 13 mg (11%) of the corresponding isomer(3-ethyl-1-(1-ethylpropyl)-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole)was also isolated.

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   98)    3-ethyl-1-(1-ethylpropyl)-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,    LC/MS (EI) t_(R) 4.76(Method C), m/z 437.1 (M⁺+1)-   100)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-indazole,    LC/MS (EI) t_(R) 4.36 (Method C), m/z 465.2 (M⁺+1)-   101)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-2-(tetrahydro-2H-pyran-2-ylmethyl)-2H-indazole,    LC/MS (EI) t_(R) 4.3 (Method C), m/z 465.2 (M⁺+1)-   102)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-2-(2-pyrrolidin-1-ylethyl)-2H-indazole,    LC/MS (EI) t_(R) 4.11 (Method C), m/z 464.1 (M⁺+1)-   104)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(2-pyrrolidin-1-ylethyl)-1H-indazole,    LC/MS (EI) t_(R) 4.24 (Method C), m/z 464.1 (M⁺+1)

Example 53 108)N,3-Diethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxaride

Isocyanatoethane (0.014 mL, 0.18 mmol) was added to a solution of3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole (50mg, 0.14 mmol) in pyridine (2 mL) and the mixture was heated at 100° C.for 16 hours. Upon cooling, water and ethyl acetate were added and theproduct was washed once with 0.1 N HCl, once with water and once withbrine. The combined organics were dried, the solvent was removed, andthe reside was purified by column chromatography on silica gel, elutingwith 20% ethyl acetate in hexanes for 5 minutes, a linear gradient to50% ethyl acetate in hexanes over 15 minutes, and then 50% ethyl acetatefor an additional 10 minutes, to afford 32 mg (54%) ofN,3-diethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxamide.LC/MS (EI) t_(R) 4.33 (Method C), m/z 438.2 (M⁺+1), ¹H NMR (CDCl₃) δ 1.0(t, 3H), 1.4 (t, 3H), 2.9 (t, 2H), 3.0 (s, 3H), 3.4 (m, 2H), 6.5 (s,1H), 7.0 (d, 1H), 7.1 (s, 1H), 7.4 (d, 2H), 7.5 (m, 1H), 7.8 (s, 1H),7.9 (d, 2H), 8.4 (s, 1H).

The following compounds were synthesized in a similar manner withdifferent starting materials:

-   105)    N-(sec-butyl)-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxamide,    LC/MS (EI) t_(R) 5.04 (Method A), m/z 466.1 (M⁺+1)-   107)    N-cyclopentyl-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxamide,    LC/MS (EI) t_(R) 5.34 (Method A), m/z 478.2 (M⁺+1)-   109)    3-ethyl-N-(2-furylmethyl)-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxamide,    LC/MS (EI) t_(R) 4.6 (Method A), m/z 490.2 (M⁺+1).

Example 54 103) Isopropyl3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxylate

A mixture of3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole (50mg, 0.14 mmol), tetrahydrofuran (2 mL), triphenylphospine (71.6 mg, 0.27mmol), and (3S)-tetrahydrofuran-3-ol (21.8 μL, 0.27 mmol) was stirred atroom temperature, and diisopropyl azodicarboxylate (53.7 μL, 0.27 mmol)was added. The resulting mixture was stirred at room temperature for 16hours. The crude product was then absorbed onto silica gel and isolatedby flash chromatography using a hexane:ethyl acetate (1:1) methanolgradient (0-10%) over 10 minutes (20 mL/min flow rate) to provide 40 mg(63%) of Isopropyl3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxylate.LC/MS (EI) t_(R) 2.27 (Method C), m/z 453.1 (M⁺+1), ¹H NMR (CDCl₃) δ 1.4(m, 9H); 2.9 (m, 2H); 3.0 (s, 3H); 5.2 (m, 1H); 6.7 (s, 1H); 7.1 (d,1H); 7.5 (d, 2H); 7.6 (d, 1H); 7.7 (d, 2H); 7.8 (s, 1H); 8.1 (m, 1H).

Example 55 110)3-Ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyrimidin-2-yl-1H-indazole

A mixture of3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole (50mg, 0.14 mmol), tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01mmol), 2-bromopyrimidine (26 mg, 0.16 mmol),9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (16 mg, 0.03 mmol),sodium tert-butoxide (19.7 mg, 0.21 mmol) and toluene (2.3 mL) wassubjected to microwave irradiation (300 watts, 140° C.) for 300 secondsin a 10 mL sealed tube. The solvent was removed and the crude productabsorbed onto silica gel. The residue was purified by columnchromatography using as eluent 10% ethyl acetate in hexanes for 10minutes, then a gradient to 50% ethyl acetate in hexanes at 20 minutes,then 50% for 5 minutes, then 100% at 35 minutes to provide 42 mg (70%)of3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyrimidin-2-yl-1H-indazole.LC/MS (EI) t_(R) 3.82 (Method C), m/z 445.1 (M⁺+1), ¹H NMR (CDCl₃) δ 1.5(t, 3H); 3.0 (s, 3H); 3.1 (q, 2H); 6.6 (s, 1H); 7.1 (d, 2H); 7.6 (d,2H); 7.7 (d, 1H); 7.8 (d, 1H); 7.9 (m, 2H); 8.7 (m, 3H).

The following compound was synthesized in a similar manner withdifferent starting materials:

-   118)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyridin-2-yl-1H-indazole,    LC/MS (EI) t_(R) 5.37 (Method A), m/z 444.2 (M⁺+1)

Example 56 a) Synthesis of 1-(2,6-difluoropyridin-3-yl)propan-2-ol

2,6-difluoropyridine (5.0 mL, 0.0551 mol) in tetrahydrofuran (55 mL) wasslowly added to a 1-necked flask containing lithium diisopropylamide (31mL, 1.8 M in tetrahydrofuran) at −78° C. The reaction was stirred atthis temperature for 30 minutes and then propionaldehyde (3.96 mL,0.0551 mol) was added. After stirring at this temperature for anadditional 30 minutes, the reaction was quenched by the addition of asaturated solution of ammonium chloride (20 mL). The product wasextracted with diethylether, and purified by column chromatography usingas eluent 10% ethyl acetate in hexanes to provide 6.7 g (70%) of1-(2,6-difluoropyridin-3-yl)propan-2-ol.

b) Synthesis of 1-(2,6-difluoropyridin-3-yl)propan-1-one

A mixture of 1-(2,6-difluoropyridin-3-yl)propan-2-ol (6.3 g, 0.036 mol)pyridinium chlorochromate (27.1 g, 0.126 mol) and chloroform (320 mL)was stirred at room temperature for 16 hours. The mixture was filteredthrough silica gel, which was then washed with dichloromethane, toafford 4.8 g (77%) of 1-(2,6-difluoropyridin-3-yl)propan-1-one.

Example 57 Synthesis of3-Ethyl-6-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine

A mixture of tert-butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazinecarboxylate(3.8 g, 0.018 mol) and trifluoroacetic acid (20 mL, 0.3 mol) werestirred in dichloromethane (20 mL) for 90 minutes. The mixture wasconcentrated, and the residue was taken up in acetonitrile (30 mL).1-(2,6-difluoropyridin-3-yl)propan-1-one (2.34 g, 0.0137 mol) was thenadded, and the resulting mixture was stirred at 75° C. for 72 hours.After cooling to room temperature, the mixture was concentrated, and theresidue was purified by flash chromatography on silica gel using a10-50% hexane:ethyl acetate gradient (flow rate 20 mL/min). The organicswere combined and the crude product was then extracted with ethylacetate. The combined extracts were washed with saturated sodiumbicarbonate and then concentrated to afford 2.86 g (83.9%) of3-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridineas a white solid. LC/MS (EI) t_(R) 3.5 (Method E), m/z 250 (M⁺+1).

The following compound was prepared in a similar fashion with differentstarting materials:

-   3-Ethyl-6-fluoro-1-isopropyl-1H-pyrazolo[3,4-b]pyridine.

Example 58 Synthesis of3-Ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carbonitrile

A mixture of3-ethyl-6-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine(2.92 g, 0.0117 mol), sodium cyanide (3.9 g, 0.079 mol),tetra-N-butylammonium bromide (7.6 g, 0.023 mol) and dimethyl sulfoxide(60 mL) was heated at 150° C. for 2 hours. After cooling, the productwas extracted using ethyl acetate (300 mL). The extract was washed withwater (5×50 mL) and brine (50 mL), and then concentrated to provide thecrude product as a brown solid, which was purified by flashchromatography on silica gel using a 10-50% hexane:ethyl acetategradient over 15 minutes (flow rate 20 mL/min) to afford 2.22 g (73.9%)of3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carbonitrileas an off-white solid, which was used without further purification.LC/MS (EI) t_(R) 3.57 (Method E), m/z 257.2 (M⁺+1).

The following compound was prepared in a similar fashion with differentstarting materials:

-   3-Ethyl-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-6-carbonitrile.

Example 59 Synthesis of1-[3-Ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-yl]ethanone

Methyltriphenylphosphonium bromide (4.64 g, 0.0130 mol) and lithiumiodide (0.48 g, 0.0036 mol) were mixed in tetrahydrofuran (70 mL) in a3-necked flask under an atmosphere of nitrogen. The flask was wrapped inaluminum foil to exclude light, and chilled to 0° C. n-Butyllithium (5.8mL, 2.5 M in hexanes, 0.014 mol) was then added and the resultingmixture stirred for 30 minutes. A solution of3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carbonitrile(1.85 g, 7.22 mmol) in tetrahydrofuran (19.8 mL) was then added and thereaction stirred at 50° C. for 90 minutes. After cooling to roomtemperature, the product was extracted using dichloromethane (250 mL).The extract was washed brine and concentrated to afford the crudeproduct as a semi-solid, which was purified by flash chromatography onsilica gel using a 10-50% hexane:ethyl acetate gradient over 10 minutes(flow rate 20 mL/min). Concentration of the organics afforded 1.39 g(70.4%) of1-[3-Ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-yl]ethanoneas a colorless oil. LC/MS (EI) t_(R) 3.72 (Method E), m/z 274.1 (M⁺+1).All reagents were stored in a desiccator prior to use.

The following compound was prepared in a similar fashion with differentstarting materials:

-   1-(3-Ethyl-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-6-yl)ethanone.

Example 60 116)3-ethyl-6-{1-[4-methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1(tetrahydro-2H-pyran)-1H-indazole

3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole(0.18 g 0.49 mmol) in N,N-dimethylforrnamide (6 mL) was added to amixture of sodium hydride (29 mg, 60% in mineral oil, 0.74 mmol) andN,N-dimethylformamide (6 mL) under an atmosphere of argon, and theresulting mixture was stirred for 30 minutes. 4-iodotetrahydro-2H-pyran(0.16 g, 0.74 mmol) in N,N-dimethylformamide (6 mL) was then added andthe reaction was heated at 60° C. for 50 hours. After cooling, thereaction mixture was concentrated and the residue diluted withwater/acetonitrile (40 mL) and filtered (0.45 μm). The product waspurified by preparative HPLC using a gradient of 20-80%acetonitrile:water (with 0.1% formic acid and a flow rate of 45 mL/minto afford 10 mg (4.6%) of3-ethyl-6-{1-[4-methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1(tetrahydro-2H-pyran)-1H-indazoleas a yellow solid. LC/MS (EI) t_(R) 4.54 (Method A), m/z 451.2 (M⁺+1).¹H NMR (CDCl₃) δ 1.4 (t, 3H); 1.9 (d, 2H); 2.4 (m, 2H); 3.0 (m, 1H); 3.1(s, 3H); 3.6 (m, 3H); 4.1 (d, 2H); 4.5 (m, 1H); 6.6 (s, 1H); 6.9 (d,1H); 7.2-7.3 (m, 3H); 7.5-7.7 (m, 2H); 7.8-7.9 (m, 2H).

The following compounds were made using a similar procedure usingdifferent starting materials:

-   117)    1-(difluoromethyl)-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,    LC/MS (EI) t_(R) 4.21 (Method A), m/z 417.1 (M⁺+1)-   119)    1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,    LC/MS (EI) t_(R) 5.19 (Method A), m/z 491.1 (M⁺+1)-   120)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-3-yl)-1H-indazole,    LC/MS (EI) t_(R) 4.02 (Method A), m/z 437.2 (M⁺+1)-   121) Tert-butyl    3-(3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazol-1-yl)pyrrolidine-1-carboxylate,    LC/MS (EI) t_(R) 4.97 (Method B), m/z 436.2 (M⁺+1).

Example 61 112)1-cyclopropyl-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole

3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole (20mg, 0.054 mmol), cyclopropylboronic acid (14 mg, 0.16 mmol), cupricacetate (20 mg, 0.11 mmol), triethylamine (0.038 mL, 0.27 mmol),pyridine (0.035 mL, 0.44 mmol), and tetrahydrofuran (2.0 mL) were addedto a 10 mL sealed tube. The mixture was subjected to microwave radiation(300 watts, 140° C.) for 10 minutes. The solvent was removed and theresidue was extracted with ethyl acetate (10 mL). The extract was washedwith saturated sodium bicarbonate solution (2×50 mL). Concentrationafforded 22 mg (40%) of1-cyclopropyl-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole.LC/MS (EI) t_(R) 4.15 (Method A), m/z 407.1 (M⁺+1). ¹H NMR (CDCl₃) δ 1.1(m, 4H); 1.4 (t, 3H); 2.9 (m, 2H); 3.1 (s, 3H); 3.5 (m, 1H): 6.5 (s,1H); 6.9 (d, 1H); 7.4 (s, 1H); 7.5 (d, 1H); 7.6 (d, 2H); 7.8 (s, 1H);7.9 (d, 2H).

The following compounds were made using a similar procedure usingdifferent starting materials:

-   106)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyridin-3-yl-1H-indazole,    LC/MS (EI) t_(R) 3.92 (Method C), m/z 444.2 (M⁺+1)-   111)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyrimidin-5-yl-1H-indazole,    LC/MS (EI) t_(R) 3.41 (Method C), m/z 445.1 (M⁺+1)-   118)    3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyridin-2-yl-1H-indazole,    LC/MS (EI) t_(R) 5.37 (Method A), m/z 444.2 (M⁺+1).

Example 62 Synthesis of 1,3-Diethyl-1H-indazole-6-carboxylic acidmethoxy-methyl-amide

A mixture of potassium tert-butoxide (0.144 g, 1.28 mmol) and iodoethane(0.20 g, 1.28 mmol) in THF (1 mL) was added to a solution of3-ethyl-1H-indazole-6-carboxylic acid methoxy-methyl-amide (0.20 g, 0.86mmol) in THF (3 mL) and the resulting mixture stirred at roomtemperature for 16 hours. Ethyl acetate (30 mL) was then added and theproduct was extracted with 0.5 N HCl (10 mL). The aqueous layer was thenre-extracted with ethyl acetate (30 mL). The organics were combined,dried, filtered and concentrated to afford 250 mg of1,3-diethyl-1H-indazole-6-carboxylic acid methoxy-methyl-amide that wasused without further purification.

The following compounds were made using a similar procedure usingdifferent starting materials:

-   3-ethyl-1-(2-methoxyethyl)-1H-indazole-6-carboxylic acid    methoxy-methyl-amide,-   3-ethyl-1-isopropyl-1H-indazole-6-carboxylic acid    methoxy-methyl-amide,-   1-cyclopropylmethyl-3-ethyl-1H-indazole-6-carboxylic acid    methoxy-methyl-amide,-   1-cyclopentyl-1H-indazole-6-carboxylic acid methoxy-methyl-amide.

Example 63 Synthesis of 1-(1,3-Diethyl-1H-indazol-6-yl)-ethanone

1,3-Diethyl-1H-indazole-6-carboxylic acid methoxy-methyl-amide (0.22 g,0.86 mmol) was dissolved in tetrahydrofuran (8 mL) and cooled to −70° C.Methylmagnesium chloride (2 mL, 3M in tetrahydrofuran, 0.06 mol) wasadded dropwise and the resulting mixture was stirred for 30 minutes at−70° C. After warming to room temperature, the mixture was stirred for afurther 3 minutes, then quenched by the addition of a chilled saturatedsolution of ammonium chloride. Ethyl acetate (150 mL) and water (40 mL)were then added and the product was extracted. The aqueous layer wasre-extracted with ethyl acetate (75 mL). The organic layers werecombined, dried, filtered, and concentrated to afford 200 mg of1-(1,3-Diethyl-1H-indazol-6-yl)-ethanone.

The following compounds were made using a similar procedure usingdifferent starting materials:

-   1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-ethanone,-   1-(3-ethyl-1H-indazol-6-yl)-ethanone,-   1-[1-(cyclopropylmethyl)-3-ethyl-1H-indazol-6-yl]-ethanone,-   1-[3-ethyl-1-(2-methoxyethyl)-1H-indazol-6-yl)-ethanone,-   1-(3-ethyl-1-isopropyl-1H-indazol-6-yl)-ethanone.

Example 64 Synthesis of(2E)-1-(1,3-diethyl-1H-indazol-6-yl)-3-(dimethylamino)prop-2-en-1-one

1,1-dimethoxy-N,N-dimethylmethanamine (0.891 g, 0.0075 mol) was added toa solution of 1-(1,3-Diethyl-1H-indazol-6-yl)-ethanone (0.187 mg, 8.64mmol) in N,N-dimethylformamide (8 mL), and the resulting mixture wasshaken at 120° C. for 16 hours. 1,1-dimethoxy-N,N-dimethylmethanamine(0.618 g, 0.0052 mol) was added, and the reaction was refluxed at 140°C. for a further 16 hours. The solvent was removed in vacuo, and theresidue extracted with ethyl acetate (30 mL) and water (10 mL). Theaqueous layer was re-extracted with ethyl acetate (30 mL). The organiclayers were combined, dried, filtered and concentrated. The resultingcrude product was purified by silica-gel chromatography, using an eluentgradient of 0.25-0.5% methanol in dichloromethane (mobile phasecontained 0.5% ammonium hydroxide solution) to afford 35 mg of(2E)-1-(1,3-diethyl-1H-indazol-6-yl)-3-(dimethylamino)prop-2-en-1-one.

The following compounds were made using a similar procedure usingdifferent starting materials:

-   (2E)-1-[1-(cyclopropylmethyl)-3-ethyl-1H-indazol-6-yl)-3-(dimethylamino)prop-2-en-1-one,-   (2E)-3-(dimethylamino)-1-(3-ethyl-1-isopropyl-1H-indazol-6-yl)-3-(dimethylamino)prop-2-en-1-one,-   (2E)-3-(dimethylamino)-1-(3-ethyl-1-(2-methoxyethyl)-1H-indazol-6-yl)-3-(dimethylamino)prop-2-en-1-one,-   (2E)-1-[1-(cyclopentyl)-3-ethyl-1H-indazol-6-yl)-3-(dimethylamino)prop-2-en-1-one,-   (2E)-3-(dimethylamino)-1-(3-ethyl-1-isopropyl-1H-pyrazaol[3,4-b]-pyridin-6-yl)-prop-2-en-1-one,-   (2E)-3-(dimethylamino)-1-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazaol[3,4-b]-pyridin-6-yl]-prop-2-en-1-one.

Example 65 129)2-{4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenyl}propan-2-ol

Methylmagnesium chloride (0.09 mL, 3 M in tetrahydrofuran, 0.3 mmol) intetrahydrofuran (0.09 mL) was added dropwise to a solution of methyl4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzoate(36 mg, 0.093 mmol) in tetrahydrofuran (4 mL) under an atmosphere ofargon at −78° C. The reaction was allowed to warm to room temperaturewith stirring over 1 hour. A further charge of methylmagnesium chloride(1.2 mL, 3 M in tetrahydrofuran, 4 mmol) was added and the reaction wasstirred for a further 30 minutes. The reaction was cooled to 0° C. and asaturated solution of ammonium chloride was slowly added. The mixturewas then added to water, and the product was extracted twice with ethylacetate. The organic layers were combined, dried, and concentrated. Theresidue was purified on silica gel using a 20-50% ethyl acetate/hexanegradient to afford 12.9 mg (36%) of2-{4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenyl}propan-2-ol.LC/MS (EI) t_(R) 4.30 (Method A), m/z 387.2 (M⁺+1).

Example 66 173)3-{5-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenol

6-{1-[4-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine(290 mg, 0.60 mmol) and ethanol (30 mL) were added to a Parr bottle. 10%Pd/C (150 mg, 0.14 mmol) was added, and the mixture was shaken under anatmosphere of hydrogen (45 psi) for 4 hours. The reaction was degassedunder reduced pressure, flushed with argon for 5 minutes, filteredthrough Celite and concentrated to yield 0.23 g3-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenolas an oil. LC/MS (EI) t_(R) 2.87 (Method E), m/z 390.2 (M⁺+1). ¹H NMR(CDCl₃) δ 1.4 (t, 3H); 1.7 (m, 2H); 2.2 (m, 2H); 3.0 (q, 2H); 3.5 (t,2H); 4.0 (m, 2H); 4.5 (m, 1H); 6.7-6.9 (m, 3H); 7.0 (s, 1H); 7.2 (m,1H); 7.3 (d, 2H); 7.7 (s, 1H); 8.0 (m, 1H).

The following compound was prepared using a similar procedure withdifferent starting materials:

-   138)    3-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenol,    LC/MS (EI) t_(R) 2.7 (Method E), m/z 345.2 (M⁺+1)-   143)    4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenol,    LC/MS (EI) t_(R) 2.83 (Method E), m/z 345.2 (M⁺+1)-   172)    4-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenol,    LC/MS (EI) t_(R)×2.92 (Method E), m/z 390.2 (M⁺+1).

Example 67 146)1-cyclopropyl-3-ethyl-6-{1-[3-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-1H-indazole

Potassium carbonate (60.2 mg, 4.36 mmol), and 1-bromo-2-methoxyethane(40.9 μl, 4.36 mmol) were added to a solution of3-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenol (50mg, 1.0 mmol) in N, N-dimethylformamide (3 mL), and the resultingmixture was stirred at 60° C. for 16 hours, then at 80° C. for a further24 hours. After cooling, the reaction mixture was diluted by theaddition of water/acetonitrile (1.0 mL), which was then filtered. Thefiltrate was purified by preparative HPLC (C18 column, 30×100 mm) usinga gradient of 35-80% acetonitrile:water (with 0.1% formic acid) as theeluent at a flow rate of 45 mL/min to afford 24 mg (40%) of1-cyclopropyl-3-ethyl-6-{1-[3-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-1H-indazole.LC/MS (EI) t_(R) 4.3 (Method E), m/z 403.2 (M⁺+1). ¹H NMR (CDCl₃) δ 1.0(m, 4H); 1.4 (t, 3H); 3.0 (q, 2H) 3.5 (m, 4H); 3.7 (d, 2H); 4.1 (d, 2H)6.6 (s, 1H); 6.8-6.9 (dd, 2H); 7.1 (m, 2H); 7.2 (m, 1H); 7.3 (s, 1H);7.5 (d, 1H); 7.8 (s, 1H).

The following compounds were prepared using a similar procedure withdifferent starting materials:

-   135)    1-cyclopentyl-3-ethyl-6-(1-{4-[(2-methoxyethoxy)methyl]phenyl}-1H-pyrazol-5-yl)-1H-indazole,    LC/MS (EI) t_(R) 4.56 (Method A), m/z 445.3 (M⁺+1)-   148)    1-cyclopropyl-3-ethyl-6-{1-[4-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-1H-indazole,    LC/MS (EI) t_(R) 4.02 (Method E), m/z 403.2 (M⁺+1)-   174)    6-{1-[3-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,    LC/MS (EI) t_(R) 3.58 (Method E), m/z 448.2 (M⁺+1)-   175)    6-{1-[4-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine    , LC/MS (EI) t_(R) 3.83 (Method E), m/z 448.2 (M⁺+1)-   176)    2-(3-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenoxy)ethanol,    LC/MS (EI) t_(R) 2.74 (Method E), m/z 434.2 (M⁺+1)-   177)    2-(4-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl]phenoxy)ethanol,    LC/MS (EI) t_(R) 2.75 (Method E), m/z 434.2 (M⁺+1).

Example 68 95)6-[1-(1-acetylpiperidin-4-yl)-1H-pyrazol-5-yl]-1-cyclopentyl-3-ethyl-1H-indazole

Acetyl chloride (7.8 μL, 0.11 mmol) was slowly added to a mixture of1-cyclopentyl-3-ethyl-6-(1-piperidin-4-yl-1H-pyrazol-5-yl)-1H-indazole(20 mg, 0.055 mmol), triethylamine (15 μL, 0.11 mmol) in methylenechloride (2 mL), and the reaction was stirred for 16 hours at roomtemperature. Methylene chloride was added and the organic layer waswashed with saturated sodium bicarbonate, water, then brine, dried,filtered and concentrated. The residue was dissolved in ethyl acetateand purified by silica gel column chromatography using 100% ethylacetate as the eluent to afford 18 mg (81%) of6-[1-(1-acetylpiperidin-4-yl)-1H-pyrazol-5-yl]-1-cyclopentyl-3-ethyl-1H-indazole.LC/MS (EI) t_(R) 4.29 (Method C), m/z 406.3 (M⁺+1).

Example 69 128){4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenyl}methanol

A solution of diisobutylaluminum hydride (0.19 mL, 1.5 M in toluene,0.28 mmol) in toluene (0.19 mL) was added dropwise to a solution ofmethyl4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzoate(36 mg, 0.093 mmol) in tetrahydrofuran (5 mL) under an atmosphere ofargon at −78° C. The reaction was allowed to warm to room temperatureover a period of 1 hour. The mixture was then chilled to −40° C. andmethanol (4 mL) was slowly added. Again, the reaction was allowed towarm slowly to room temperature, then it was poured into a mixture ofethyl acetate and water. The product was extracted (3×ethyl acetate),and the combined organics were dried and concentrated. The residue waspurified by silica gel column chromatography using 50% ethyl acetate inhexanes as the eluent to afford 22.6 mg (68%) of4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenyl}methanol.LC/MS (EI) t_(R) 3.19 (Method A), m/z 359.2 (M⁺+1). ¹H NMR (CDCl₃) δ 1.0(m, 4H); 1.2 (t, 3H); 2.5 (m, 1H); 2.8 (m, 2H); 3.2 (m, 1H); 4.5 (s,2H); 6.5 (s, 1H); 6.9 (t, 1H); 7.0-7.2 (m, 5H); 7.5 (d, 1H); 7.6 (s,1H).

Example 70 In Vitro Measurement of Type 4 Phosphodiesterase

Enzyme Preparation:

Human PDE4 was obtained from baculovirus-infected Sf9 cells thatexpressed the recombinant enzyme. The cDNA encoding hPDE-4D6 wassubcloned into a baculovirus vector. Insect cells (Sf9) were infectedwith the baculovirus and cells were cultured until protein wasexpressed. The baculovirus-infected cells were lysed and the lysate wasused as source of hPDE-4D6 enzyme. The enzyme was partially purifiedusing a DEAE ion exchange chromatography. This procedure can be repeatedusing cDNA encoding other PDE-4 enzymes.

Assay:

Type 4 phosphodiesterases convert cyclic adenosine monophosphate (cAMP)to 5′-adenosine monophosphate (5′-AMP). Nucleotidase converts 5′-AMP toadenosine. Therefore the combined activity of PDE4 and nucleotidaseconverts cAMP to adenosine. Adenosine is readily separated from cAMP byneutral alumina columns. Phosphodiesterase inhibitors block theconversion of cAMP to adenosine in this assay; consequently, PDE4inhibitors cause a decrease in adenosine.

Cell lysates (40 μl) expressing hPDE-4D6 were combined with 50 μl ofassay mix and 10 μl of inhibitors and incubated for 12 min at roomtemperature. Final concentrations of assay components were: 0.4 μgenzyme, 10 mM Tris-HCl (pH 7.5), 10 mM MgCl₂, 3 uM cAMP, 0.002 U5′-nucleotidase, and 3×10⁴ cpm of [3H]cAMP. The reaction was stopped byadding 100 μl of boiling 5 mM HCl. An aliquot of 75 μl of reactionmixture was transferred from each well to alumina columns (Multiplate;Millipore). Labeled adenosine was eluted into an OptiPlate by spinningat 2000 rpm for 2 min; 150 μl per well of scintillation fluid was addedto the OptiPlate. The plate was sealed, shaken for about 30 min, and cpmof [³H]adenosine was determined using a Packard Topcount 96 counter.

All test compounds were dissolved in 100% DMSO and diluted into theassay such that the final concentration of DMSO is 0.1%. DMSO does notaffect enzyme activity at this concentration. A decrease in adenosineconcentration is indicative of inhibition of PDE activity. Thisprocedure may be used to screen compounds of the present invention fortheir ability to inhibit PDE4. pIC₅₀ values may be determined byscreening 6 to 12 concentrations of compound ranging from 0.1 nM to10,000 nM and then plotting drug concentration versus ³H-adenosineconcentration. Prism® may be used to estimate pIC₅₀ values.

Compounds of the invention show activity in the range of 10 nM-5000 nMIC50 in the assay.

Example 71 Passive Avoidance in Rats, an In Vivo Test for Learning andMemory

The test may be performed as previously described [Zhang, H.-T.,Crissman, A. M., Dorairaj, N. R., Chandler, L. J., and O'Donnell, J. M.,Neuropsychopharmacology, 2000, 23, 198-204]. The apparatus (ModelE10-16SC, Coulbourn Instruments, Allentown, Pa.) consisted of atwo-compartment chamber with an illuminated compartment connected to adarkened compartment by a guillotine door. The floor of the darkenedcompartment consisted of stainless steel rods through which an electricfoot-shock may be delivered from a constant current source. Allexperimental groups may be first habituated to the apparatus the daybefore the start of the experiment. During the training, the rat (MaleSpraque-Dawley (Harlan) weighing 250 to 350 g) may be placed in theilluminated compartment facing away from the closed guillotine door for1 minute before the door was raised. The latency for entering thedarkened compartment may be recorded. After the rat enters the darkenedcompartment, the door may be closed and a 0.5 mA electric shock wasadministered for 3 seconds. Twenty-four hours later, the rat may beadministered 0.1 mg/kg of the test compound or saline, 30 minutes priorto the injection of saline or test compound (dosed from 0.1 to 2.5mg/kg, i.p.), which was 30 minutes before the retention test starts. Therat may be again placed in the illuminated compartment with theguillotine door open. The latency for entering the darkened compartmentmay be recorded for up to 180 seconds, at which time the trial wasterminated.

All data may be analyzed by analyses of variance (ANOVA); individualcomparisons were made using Kewman-Keuls tests. Naive rats required lessthan 30 seconds, on average, to cross from the illuminated compartmentto the darkened compartment.

Example 72 Radial Arm Maze Task in Rats, an In Vivo Test for Learningand Memory

The test may be performed as previously described [Zhang, H.-T.,Crissman, A. M., Dorairaj, N. R., Chandler, L. J., and O'Donnell, J. M.,Neuropsychopharmacology, 2000, 23, 198-204. ]. Five days after initialhousing, rats (male Spraque-Dawley (Harlan) weighing 250 to 350 g) maybe placed in the eight-arm radial maze (each arm was 60×10×12 cm high;the maze was elevated 70 cm above the floor) for acclimation for twodays. Rats may be then placed individually in the center of the maze for5 minutes with food pellets placed close to the food wells, and then,the next day, in the wells at the end of the arms; 2 sessions a day maybe conducted. Next, four randomly selected arms may be then baited withone pellet of food each. The rat may be restricted to the centerplatform (26 cm in diameter) for 15 seconds and then allowed to movefreely throughout the maze until it collected all pellets of food or 10minutes passed, whichever came first. Four parameters may berecorded: 1) working memory errors, i.e., entries into baited arms thathad already been visited during the same trial; 2) reference memoryerrors, i.e., entries into unbaited arms; 3) total arm entries; and 4)the test duration (seconds), i.e., the time spent in the collection ofall the pellets in the maze. If the working memory error is zero and theaverage reference memory error is less than one in five successivetrials, the rats may begin the drug tests. The test compound or salinemay be injected 15 minutes prior to vehicle or test agent, which may begiven 45 minutes before the test. Experiments are performed in a lightedroom, which contained several extra-maze visual cues.

All data may be analyzed by analyses of variance (ANOVA); individualcomparisons were made using Kewman-Keuls tests.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

While the invention has been illustrated with respect to the productionand of particular compounds, it is apparent that variations andmodifications of the invention can be made without departing from thespirit or scope of the invention. Upon further study of thespecification, further aspects, objects and advantages of this inventionwill become apparent to those skilled in the art.

1. A compound according to Formulas III, VI, IX or X:

wherein X is CH or N; L is a single bond; C₁-C₆ straight chain orbranched alkylene, wherein a CH₂ group is optionally replaced by O, NH,NR¹, or S, which is unsubstituted or substituted one or more times byoxo, halogen, hydroxy, cyano or combinations thereof; (CH₂)_(n)CONH;(CH₂)_(n)OCONH; (CH₂)_(n)CON(C₁₋₆-alkyl); (CH₂)_(n)NHCO;(CH₂)_(n)CONHSO₂; (CH₂)_(n)SO₂NH; (CH₂)_(n)SO₂; or (CH₂)_(n)CO₂; n is 0to 3; R³ is H, alkyl having 1 to 8 carbon atoms, which is unsubstitutedor substituted one or more times by halogen, oxo, or combinationsthereof wherein optionally one or more —CH₂CH₂— groups are replaced ineach case by —CH═CH— or —C≡C— groups, cycloalkyl having 3 to 8 carbonatoms, which is unsubstituted or substituted one or more times byhalogen, oxo, alkyl, or combinations thereof, aryl having 6 to 14 carbonatoms, which is unsubstituted or substituted one or more times byhalogen, alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy,nitro, methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino,—CO—N(R¹⁰)₂, —SO₂—N(R¹⁰)₂, hydroxyalkyl, hydroxyalkoxy, alkoxyalkoxy,alkoxyalkoxyalkyl, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio,alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl,phenyl, halogenated phenyl, phenoxy, benzyloxy, acyloxy, acylamido,furanyl which is unsubstituted or substituted by halogen, C₁₋₄-alkyl,C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl, pyrrolyl which isunsubstituted or substituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy,C₂₋₈-alkoxycarbonyl, and/or benzyl, pyrazolyl which is unsubstituted orsubstituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl,and/or benzyl, isoxazolyl which is unsubstituted or substituted byhalogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl,imidazolyl which is unsubstituted or substituted by halogen, C₁₋₄-alkyl,C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl, pyridinyl which isunsubstituted or substituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy,C₂₋₈-alkoxycarbonyl, and/or benzyl, pyrimidinyl which is unsubstitutedor substituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl,and/or benzyl, morpholinyl which is unsubstituted or substituted byC₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or benzyl, piperadinyl which isunsubstituted or substituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/orbenzyl, piperazinyl which is unsubstituted or substituted by C₁₋₄-alkyl,C₂₋₈-alkoxycarbonyl, and/or benzyl, tetrazolyl which is unsubstituted orsubstituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or benzyl,alkylsulphonimide, arylsulphonimide wherein the aryl portion isoptionally substituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, orcombinations thereof, heterocyclic group, which is saturated, partiallysaturated or fully unsaturated, having 5 to 10 ring atoms in which atleast 1 ring atom is an N, O or S atom, which is unsubstituted orsubstituted one or more times by halogen, alkyl, hydroxy, alkoxy,halogenated alkyl, halogenated alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl,hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio,alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, phenyl,halogenated phenyl, phenoxy, acyloxy, tetrazolyl, alkylsulphonimide,arylsulphonimide, aryl, oxo, acylamido, or combinations thereof,arylalkyl having 7 to 16 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, alkyl, hydroxy, alkoxy,halogenated alkyl, halogenated alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl,hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio,alkylsulfinyl, alkylsulfinyl, arylsulfonyl, arylsulfonyl, phenyl,halogenated phenyl, phenoxy, acyloxy, acylamido, tetrazolyl,alkylsulphonimide, arylsulphonimide, or combinations thereof and/orsubstituted in the alkyl portion by halogen, oxo, cyano, or combinationsthereof, a heterocyclic-alkyl group, which is saturated, partiallysaturated or fully unsaturated, having 5 to 10 ring atoms in which atleast 1 ring atom is an N, O or S atom, which is unsubstituted orsubstituted one or more times in the heterocyclic portion by halogen,alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy, nitro,methylenedioxy, ethylenedioxy, amino, alkylamino, dialkylamino,hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl,alkylthio, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl,phenyl, halogenated phenyl, phenoxy, acyloxy, tetrazolyl,alkylsulphonimide, arylsulphonimide, aryl, oxo, or combinations thereofand/or substituted in the alkyl portion by halogen, oxo, cyano, orcombinations thereof, cycloalkylalkyl having 4 to 16 carbon atoms, whichis unsubstituted or substituted one or more times by halogen, oxo, alkylor combinations thereof, or alkoxyalkyl having 3 to 8 carbon atoms; R⁵is H, alkyl having 1 to 6 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, oxo, or combinations thereofwherein optionally one or more —CH₂CH₂— groups are replaced in each caseby —CH═CH— or —C≡C— groups, or alkoxycarbonyl (—C(═O)O-alkyl) having 2to 6 carbon atoms; R⁶ is H, alkyl having 1 to 6 carbon atoms, which isunsubstituted or substituted one or more times by halogen, oxo, hydroxyor combinations thereof wherein optionally one or more —CH₂CH₂— groupsare replaced in each case by —CH═CH— or —C≡C— groups, alkoxyalkyl having2 to 6 carbon atoms which is unsubstituted or substituted one or moretimes by halogen, oxo, or combinations thereof; alkoxycarbonyl(—C(═O)O-alkyl) having 2 to 6 carbon atoms; —CO—NR⁵R¹²; cycloalkylhaving 3 to 4 carbon atoms, which is unsubstituted or substituted one ormore times by halogen, oxo, alkyl, or combinations thereof,cycloalkylalkyl having 4 to 16 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, oxo, alkyl or combinationsthereof, aryl having 6 to 14 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, CF₃, OCF₃, alkyl, hydroxy,alkoxy, nitro, methylenedioxy, ethylenedioxy, amino, alkylamino,dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy, cyano, acyl,alkoxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, phenoxy,acylamido, and acyloxy, or combinations thereof, arylalkyl having 7 to16 carbon atoms, which is unsubstituted or substituted one or more timesby halogen, CF₃, OCF₃, alkyl, hydroxy, alkoxy, nitro, methylenedioxy,ethylenedioxy, amino, alkylamino, dialkylamino, hydroxyalkyl,hydroxyalkoxy, carboxy, cyano, acyl, alkoxycarbonyl, alkylthio,alkylsulfinyl, alkylsulfonyl, phenoxy, acylamido, and acyloxy, orcombinations thereof, a heterocyclic group, which is saturated,partially saturated or fully unsaturated, having 5 to 10 ring atoms inwhich at least 1 ring atom is an N, O or S atom, which is unsubstitutedor substituted one or more times by halogen, aryl, alkyl, alkoxy,alkoxycarbonyl, cyano, halogenated alkyl, nitro, oxo, amino, alkylamino,dialkylamino, or combinations thereof, or a heterocyclic-alkyl group,which is saturated, partially saturated or fully unsaturated, having 5to 10 ring atoms in which at least 1 ring atom is an N, O or S atom,which is unsubstituted or substituted one or more times in theheterocyclic portion by halogen, aryl, alkyl, alkoxy, cyano, halogenatedalkyl, nitro, oxo, amino, alkylamino, dialkylamino, carboxy orcombinations thereof and/or substituted in the alkyl portion by halogen,oxo, cyano, or combinations thereof; R⁷ is H, halogen, or alkyl having 1to 6 carbon atoms wherein optionally one or more —CH₂CH₂— groups arereplaced in each case by —CH═CH— or —C≡C— groups and wherein the alkylis unsubstituted or substituted one or more times by halogen; R⁸ is H,halogen, alkyl having 1 to 6 carbon atoms wherein optionally one or more—CH₂CH₂— groups are replaced in each case by —CH═CH— or —C≡C— groups andwherein the alkyl is unsubstituted or substituted one or more times byhalogen or hydroxyl, carboxy, alkoxycarbonyl having 2 to 6 carbon atoms,—CO-alkyl having 2 to 6 carbon atoms, or phenyl; R¹⁰ is H, alkyl having1 to 8 carbon atoms, which is unsubstituted or substituted one or moretimes by halogen, oxo or combinations thereof wherein optionally one ormore —CH₂CH₂— groups are replaced in each case by —CH═CH— or —C≡C—groups, or alkoxy having 2 to 8 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen; R¹¹ is H, alkyl having 1 to 6carbon atoms, which is unsubstituted or substituted one or more times byhalogen, oxo, or combinations thereof wherein optionally one or more—CH₂CH₂— groups are replaced in each case by —CH═CH— or —C≡C— groups, ora heterocyclic-alkyl group, which is saturated, partially saturated orfully unsaturated, having 5 to 10 ring atoms in which at least 1 ringatom is an N, O or S atom, which is unsubstituted or substituted one ormore times in the heterocyclic portion by halogen, aryl, alkyl, alkoxy,cyano, halogenated alkyl, nitro, oxo, amino, alkylamino, dialkylamino,carboxy or combinations thereof and/or substituted in the alkyl portionby halogen, oxo, cyano, or combinations thereof; R¹² is H, alkyl having1 to 6 carbon atoms, which is unsubstituted or substituted one or moretimes by halogen, oxo, or combinations thereof wherein optionally one ormore —CH₂CH₂— groups are replaced in each case by —CH═CH— or —C≡C—groups, cycloalkyl having 3 to 8 carbon atoms, which is unsubstituted orsubstituted one or more times by halogen, oxo, alkyl, or combinationsthereof, or a heterocyclic-alkyl group, which is saturated, partiallysaturated or fully unsaturated, having 5 to 10 ring atoms in which atleast 1 ring atom is an N, O or S atom, which is unsubstituted orsubstituted one or more times in the heterocyclic portion by halogen,aryl, alkyl, alkoxy, cyano, halogenated alkyl, nitro, oxo, amino,alkylamino, dialkylamino, carboxy or combinations thereof and/orsubstituted in the alkyl portion by halogen, oxo, cyano, or combinationsthereof; or a pharmaceutically acceptable salt thereof, apharmaceutically acceptable solvate thereof, or a solvate of apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein L is (CH₂)_(n)OCONH.
 3. A compound according to claim1, wherein R³ is aryl having 6 to 14 carbon atoms which is substitutedby at least one substituent selected from —CO—N(R¹⁰⁾ ₂, aminosulfonyl,furanyl which is unsubstituted or substituted by halogen, C₁₋₄-alkyl,C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl and/or benzyl, pyrrolyl which isunsubstituted or substituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy,C₂₋₈-alkoxycarbonyl, and/or benzyl, pyrazolyl which is substituted byhalogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl,isoxazolyl which is unsubstituted or substituted by halogen, C₁₋₄-alkyl,C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl, imidazolyl which issubstituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl,and/or benzyl, pyridinyl which is substituted by halogen, C₁₋₄-alkyl,C₁₋₄-alkoxy, C₂₋₈-alkoxycarbonyl, and/or benzyl, pyrimidinyl which isunsubstituted or substituted by halogen, C₁₋₄-alkyl, C₁₋₄-alkoxy,C₂₋₈-alkoxycarbonyl, and/or benzyl, morpholinyl which is substituted byC₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or benzyl, piperadinyl which issubstituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or benzyl,piperazinyl which is substituted by C₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl,and/or benzyl, tetrazolyl which is unsubstituted or substituted byC₁₋₄-alkyl, C₂₋₈-alkoxycarbonyl, and/or benzyl, or arylsulphonimidewherein the aryl portion is substituted by halogen or C₁₋₄-alkoxy.
 4. Acompound according to claim 1, wherein said compound is of Formula IX.5. A compound according to claim 1, wherein said compound is of FormulaIII.
 6. A compound according to claim 1, wherein said compound is ofFormula VI.
 7. A compound according to claim 1, wherein said compound isof Formula X.
 8. A compound according to claim 1, wherein R³ is ethyl,aryl which is substituted or unsubstituted or heteroaryl which issubstituted or unsubstituted, and L is a single bond.
 9. A compoundaccording to claim 1, wherein X is CH and L is a single bond.
 10. Acompound according to claim 1, wherein R³ is ethyl, aryl which issubstituted or unsubstituted or heteroaryl which is substituted orunsubstituted, L is a single bond, and X is CH.
 11. A compound accordingto claim 1, wherein R³ is aryl substituted at least once by—SO₂—N(R¹⁰)₂, alkoxyalkoxy, alkoxyalkoxyalkyl or benzyloxy.
 12. Acompound according to claim 1, wherein said compound is of Formula IIIor VI, and R⁶ alkyl having 1 to 6 carbon atoms which is substituted atleast once by hydroxy; alkoxyalkyl having 2 to 6 carbon atoms which isunsubstituted or substituted one or more times by halogen, oxo, orcombinations thereof; alkoxycarbonyl having 2 to 6 carbon atoms; or—CO—NR⁵R¹².
 13. A compound according to claim 1, wherein said compoundis of Formula III, X is CH, and L is a single bond.
 14. A compoundaccording to claim 1, wherein R³ is aryl having 6 to 14 carbon atomswhich is unsubstituted or substituted with one or more halogen, cyano,nitro, amino, alkyl, alkoxy or carboxy.
 15. A compound according toclaim 1, wherein R³ is cyclohexyl, cyclopentyl, ethyl, CH(CH₃)₂,n-propyl, n-butyl, or t-butyl.
 16. A compound according to claim 1,wherein R³ is thiazolyl, pyridyl or benzothiazolyl, which in each caseis substituted or unsubstituted.
 17. A compound according to claim 1,wherein R³ is benzyl, methylbenzyl, tert-butylbenzyl, methoxybenzyl,dimethoxybenzyl, carboxybenzyl, fluorobenzyl, difluorobenzyl,trifluoromethylbenzyl, trifluoromethoxybenzyl, chlorobenzyl,nitrobenzyl, methoxycarbonylbenzyl, or phenethyl, which in each case issubstituted or unsubstituted.
 18. A compound according to claim 1,wherein R³ is a heterocyclic-alkyl group, which is saturated, partiallysaturated or fully unsaturated, having 5 to 10 ring atoms in which atleast 1 ring atom is an N, O or S atom, and which is optionallysubstituted one or more times in the heterocyclic portion by halogen,alkyl, hydroxy, alkoxy, halogenated alkyl, halogenated alkoxy, nitro,amino, alkylamino, dialkylamino, hydroxyalkyl, hydroxyalkoxy, carboxy,cyano, or combinations thereof and/or optionally substituted in thealkyl portion by halogen, oxo, cyano, or combinations thereof.
 19. Acompound according to claim 1, wherein when R⁵ is a ring substituent itis alkyl having 1 to 3 carbon atoms, and when R⁵ is part of the —COR⁵R¹²group it is H.
 20. A compound according to claim 1, wherein saidcompound is of Formula III or VI, and R⁶ is cyclopropyl.
 21. A compoundaccording to claim 1, wherein R⁷ and R⁸ are each H.
 22. A compoundaccording to claim 1, wherein R⁷ is H, and R⁸ is H, CH₃, C₂H₅, CF₃,hydroxymethyl, 2-(2-hydroxy)propyl), carboxy, ethoxycarbonyl, CH₃CO, orphenyl.
 23. A compound according to claim 1, wherein R¹⁰ is H or alkylhaving 1 to 4 carbon atoms.
 24. A compound according to claim 1, whereinsaid compound is of Formula IX or X, and R¹¹ is methyl, ethyl,ethylpropyl, tetrahydro-2H-pyranylmethyl, or pyrrolidinylethyl.
 25. Acompound according to claim 1, wherein R¹² is methyl, ethyl,ethylpropyl, or furylmethyl.
 26. A compound according to claim 1,wherein L is a bond, CH₂, CH₂CH₂, CH₂CO, CH₂CO₂, CH₂CONH, or(CH₂)_(n)OCONH.
 27. A compound according to claim 1, wherein n is 0 or2.
 28. A compound according to claim 1, wherein said compound is ofFormula III or VI, and R⁶ is alkyl having 1 to 6 carbon atoms, or aheterocyclic group.
 29. A compound according to claim 1, wherein saidcompound is of Formula III or VI, R⁵ is ethyl, and R⁶ is isopropyl,cyclopropyl, 4-tetrahydropyranyl, or 2-pyrimidinyl.
 30. A compoundaccording to claim 1, wherein said compound is of Formula III or VI; R⁵is alkyl having 1 to 3 carbon atoms; R⁶ is cycloalkyl having 4 carbonatoms; and R³ is aryl, arylalkyl, or heterocyclic group, which in eachcase is substituted or unsubstituted.
 31. A compound according to claim1, wherein said compound is of Formula III or VI; R⁵ is alkyl having 1to 3 carbon atoms; R⁶ is cyclopropyl, isopropyl, 4-tetrahydropyranyl,2-pyrimidinyl, or 3-tetrahydrofuranyl; and R³ is aryl, arylalkyl, orheterocyclic group, which in each case is substituted or unsubstituted.32. A compound according to claim 1, wherein said compound is of FormulaIII or VI; R⁵ is CH₂CH₃; R⁶ is cyclopropyl; and R³ is phenyl which issubstituted or unsubstituted.
 33. A compound according to claim 1,wherein said compound is of Formula III or VI; R⁵ is CH₂CH₃; R⁶ iscyclopropyl, isopropyl, tetrahydropyranyl, or pyrimidinyl; R³ is aryl,arylalkyl, or heteroaryl, which in each case is substituted orunsubstituted by alkyl, alkoxy, halogenated alkoxy, carboxy, acetyl,cyano, halogen, —CO—N(R¹⁰)₂, aminosulfonyl, alkylsulfonyl, tetrazolyl,alkoxyalkoxy, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, or hydroxy; andL is a single bond.
 34. A compound according to claim 1, wherein saidcompound is of Formula III or VI; R⁵ is CH₂CH₃; R⁶ is cyclopropyl,isopropyl, tetrahydropyranyl, or pyrimidinyl; and R³ is phenyl which issubstituted or unsubstituted.
 35. A compound according to claim 1,wherein said compound is of Formula III or VI; R⁵ is CH₂CH₃; R⁶ iscyclopropyl, isopropyl, tetrahydropyranyl, or pyrimidinyl; R³ is phenylwhich is substituted or unsubstituted; and L is a single bond.
 36. Acompound according to claim 1, wherein said compound is of Formula IX orX; R³ is alkyl having 1 to 3 carbon atoms; R¹¹ is alkyl having 1 to 6carbon atoms, tetrahydro-2H-pyranylmethyl or pyrrolidinylethyl; R³ isaryl, arylalkyl, or heterocyclic group, which in each case issubstituted or unsubstituted; and L is a single bond.
 37. A compoundaccording to claim 1, wherein said compound is selected from:4-[5-(3-ethyl-2-methyl-2H-indazol-6-yl)-1H-pyrazol-1-yl]benzoic acid,1,3-diethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,1-(cyclopropylmethyl)-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,3-ethyl-1-isopropyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,3-ethyl-1-(2-methoxyethyl)-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,1-(ethoxymethyl)-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,3-ethyl-1-(1-ethylpropyl)-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,3-ethyl-2-(1-ethylpropyl)-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-2H-indazole,3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-indazole,3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-2-(tetrahydro-2H-pyran-2-ylmethyl)-2H-indazole,3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-2-(2-pyrrolidin-1-ylethyl)-2H-indazole,Isopropyl3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxylate,3-ethyl-6-(1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(2-pyrrolidin-1-ylethyl)-1H-indazole,N-(sec-butyl)-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxamide,3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyridin-3-yl-1H-indazole,N-cyclopentyl-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxamide,N,3-diethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxamide,3-ethyl-N-(2-furylmethyl)-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole-1-carboxamide,3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyrimidin-2-yl-1H-indazole,3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyrimidin-5-yl-1H-indazole,1-cyclopropyl-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,1-(3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazol-1-yl)-2-methylpropan-2-ol,3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-4-yl)-1H-1-indazole,1-(difluoromethyl)-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyridin-2-yl-1H-indazole,1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydrofuran-3-yl)-1H-indazole,Tert-butyl3-(3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazol-1-yl)pyrrolidine-1-carboxylate,1-cyclopropyl-3-ethyl-6-(1-isopropyl-1H-pyrazol-5-yl)-1H-indazole,1-cyclopropyl-3-ethyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-indazole,1-cyclopropyl-3-ethyl-6-(1H-pyrazol-5-yl)-1H-indazole,1-cyclopropyl-3-ethyl-6-(1-ethyl-1H-pyrazol-5-yl)-1H-indazole,1-cyclopropyl-3-ethyl-6-(1-pyridin-4-yl-1H-pyrazol-5-yl)-1H-indazole,2-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]quinoxaline,{4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenyl}methanol,2-{4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenyl}propan-2-ol,1-{4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenyl}-N-methylmethanesulfonamide,1-cyclopropyl-3-ethyl-6-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]-1H-indazole,1-cyclopropyl-3-ethyl-6-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl]-1H-indazole,1-cyclopropyl-6-[1-(1,1-dioxidotetrahydro-3-thienyl)-1H-pyrazol-5-yl]-3-ethyl-1H-indazole,6-(1-cyclopentyl-1H-pyrazol-5-yl)-1-cyclopropyl-3-ethyl-1H-indazole,1-cyclopropyl-3-ethyl-6-[1-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-pyrazol-5-yl]-1H-indazole,6-{1-[3-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-1-cyclopropyl-3-ethyl-1H-indazole,3-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenol,3-ethyl-1-isopropyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-pyrazolo[3,4-b]pyridine,2-{3-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenoxy}ethanol,6-{1-[4-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-1-cyclopropyl-3-ethyl-1H-indazole,3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,4-[5-(1-cyclopropyl-3-ethyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]phenol,(4-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenyl)methanol,2-(4-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenyl)propan-2-ol,1-cyclopropyl-3-ethyl-6-{1-[3-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-1H-indazole,1-cyclopropyl-3-ethyl-6-[1-(3-methoxyphenyl)-1H-pyrazol-5-yl]-1H-indazole,1-cyclopropyl-3-ethyl-6-{1-[4-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-1H-indazole,1-cyclopropyl-3-ethyl-6-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-1H-indazole,1-cyclopropyl-3-ethyl-6-(1-pyrimidin-2-yl-1H-pyrazol-5-yl)-1H-indazole,3-ethyl-1-(2-methoxypyridin-4-yl)-6-(1-pyrimidin-2-yl-1H-pyrazol-5-yl)-1H-indazole,4-[5-(3-ethyl-1-methyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzoic acid4-[5-(3-ethyl-1-methyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzenesulfonamide3-ethyl-1-methyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole4-[5-(3-ethyl-1-methyl-1H-indazol-6-yl)-1H-pyrazol-1-yl]benzonitrile4-[5-(3-ethyl-2-methyl-2H-indazol-6-yl)-1H-pyrazol-1-yl]benzenesulfonamide3-ethyl-2-methyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-2H-indazole4-[5-(3-ethyl-2-methyl-2H-indazol-6-yl)-1H-pyrazol-1-yl]benzonitrile6-{1-[4-(difluoromethoxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-1-pyrazolo[3,4-b]pyridine3-ethyl-6-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine3-ethyl-6-(1-pyridin-4-yl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine3-ethyl-6-(1-phenyl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine3-ethyl-6-(1-pyrimidin-2-yl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine3-ethyl-6-[1-(3-fluorophenyl)-1H-pyrazol-5-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine3-ethyl-6-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine3-ethyl-6-[1-(3-methoxyphenyl)-1H-1-pyrazol-5-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine6-{1-[4-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine6-{1-[3-(benzyloxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine4-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenol3-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenoland physiologically acceptable salts thereof, solvates thereof, andsolvates of physiologically acceptable salts thereof, and wherein saidcompound can be in the form of a mixture of enantiomers, a mixture ofdiastereomers, or in the form of a single enantiomer or a singlediastereomer.
 38. A pharmaceutical composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable carrier.
 39. Acomposition of claim 38, wherein the compound is provided in a unitdosage of 0.1-50 mg.
 40. A compound according to claim 1, wherein saidcompound is selected from:3-ethyl-6-{1-[3-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole3-ethyl-6-{1-[4-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole2-(3-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-yl]-1H-1-pyrazol-1-yl}phenoxy)ethanol2-(4-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-yl]-1H-pyrazol-1-yl}phenoxy)ethanoland physiologically acceptable salts thereof, solvates thereof, andsolvates of physiologically acceptable salts thereof, and wherein saidcompound can be in the form of a mixture of enantiomers, a mixture ofdiastereomers, or in the form of a single enantiomer or a singlediastereomer.
 41. A compound according to claim 1, wherein said compoundis selected from:6-{1-[3-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-1-pyrazolo[3,4-b]pyridine6-{1-[4-(2-methoxyethoxy)phenyl]-1H-pyrazol-5-yl}-3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine2-(3-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenoxy)ethanol2-(4-{5-[3-ethyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}phenoxy)ethanoland physiologically acceptable salts thereof, solvates thereof, andsolvates of physiologically acceptable salts thereof, and wherein saidcompound can be in the form of a mixture of enantiomers, a mixture ofdiastereomers, or in the form of a single enantiomer or a singlediastereomer.
 42. A compound according to claim 1, wherein said compoundis of Formula III of VI, R⁵ is alkyl having 1 to 3 carbon atoms, R⁶ isalkyl having 1 to 6 carbon atoms, or a heterocyclic group, and R³ isaryl, arylalkyl, or heteroaryl, which in each case is substituted orunsubstituted.
 43. A compound according to claim 1, wherein saidcompound is of Formula III or Formula VI; R⁵ is CH₂CH₃; R⁶ istetrahydropyranyl, or pyrimidinyl; R³ is aryl, arylalkyl, or heteroaryl,which in each case is substituted or unsubstituted; and L is a singlebond.
 44. A compound according to claim 1, wherein R³ is phenyl, benzyl,pyridinyl, pyrimidinyl, pyrazolyl, or pyrrolyl, which in each case issubstituted or unsubstituted.
 45. A compound according to claim 1,wherein said compound is of Formula IX or Formula X, and R¹¹ is alkylhaving 1 to 6 carbon atoms, tetrahydro-2H-pyranylmethyl orpyrrolidinylethyl.
 46. A compound according to claim 1, wherein saidcompound is of Formula IX or Formula X; R⁵ is CH₂CH₃; R¹¹ is methyl,tetrahydro-2H-pyranylmethyl or pyrrolidinylethyl; R³ is phenyl which ineach case is substituted or unsubstituted; and L is a single bond.
 47. Acompound according to claim 1, wherein R⁵ is alkyl having 1 to 3 carbonatoms; R⁶ is alkyl having 1 to 6 carbon atoms, or a heterocyclic group;and R³ is aryl, alkyl, or heteroaryl group, which in each case issubstituted or unsubstituted.
 48. A compound according to claim 47,wherein R⁵ is CH₂CH₃; R⁶ is isopropyl, tetrahydropyranyl, orpyrimidinyl; and R³ is phenyl, benzyl, pyridinyl, pyrimidinyl,pyrazolyl, or pyrrolyl, which in each case is substituted orunsubstituted.
 49. A compound according to claim 48, wherein R³ isphenyl, benzyl, pyridinyl, pyrimidinyl, pyrazolyl, or pyrrolyl, which ineach case is substituted or unsubstituted by alkyl, alkoxy, halogenatedalkoxy, carboxy, acetyl, cyano, halogen, —CO—N(R¹⁰)₂, aminosulfonyl,alkylsulfonyl, tetrazolyl, alkoxyalkoxy, alkoxyalkyl, hydroxyalkyl,hydroxyalkoxy, or hydroxy.
 50. A compound according to claim 1, selectedfrom:3-ethyl-1-isopropyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyrimidin-2-yl-1H-indazole,3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,3-ethyl-6-(1-pyrimidin-2-yl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,and pharmaceutically acceptable salts thereof.
 51. A compound accordingto claim 50, wherein said compound is3-ethyl-1-isopropyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,or a pharmaceutically acceptable salt thereof.
 52. A compound accordingto claim 50, wherein said compound is3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyrimidin-2-yl-1H-indazole,or a pharmaceutically acceptable salt thereof.
 53. A compound accordingto claim 50, wherein said compound is3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,or a pharmaceutically acceptable salt thereof.
 54. A compound accordingto claim 50, wherein said compound is3-ethyl-6-(1-pyrimidin-2-yl-1H-pyrazol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,or a pharmaceutically acceptable salt thereof.
 55. A compound accordingto claim 37, wherein said compound is3-ethyl-1-isopropyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole,or a pharmaceutically acceptable salt thereof.
 56. A compound accordingto claim 37, wherein said compound is3-ethyl-1-isopropyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-pyrazolo[3,4-b]pyridine,or a pharmaceutically acceptable salt thereof.
 57. A compound accordingto claim 37, wherein said compound is3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine,or a pharmaceutically acceptable salt thereof.